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Predictive factors for response to cytotoxic treatment in advanced breast cancer. A review
Johanna Sjöström and Carl Blomqvist

For as long as cytotoxic treatment has been used in cancer the question has been asked: Why do some patients respond to therapy and others do not? The identification and better understanding of factors predicting response to chemotherapy might also help toward understanding the basic mechanisms behind response to cytotoxic agents in malignant disease. It would also assist the clinician in selecting the right candidates for chemotherapy and spare the others from unnecessary toxicity.
In vitro, breast cancer cell lines most likely to respond to chemotherapy are those with a short doubling time and no estrogen receptor (1). In vivo, the outcome is much more complicated and depends on several known and unknown host, tumour and biological factors which may also interact with one and other. Since 1970’s many studies have been performed in an effort to discover which factors might predict response to chemotherapy in breast cancer. Despite continuous work, for several decades there is a paucity of convincing data on this issue. This article concentrates on factors predicting response to cytotoxic treatment in advanced breast cancer and, partly, also in the neoadjuvant setting, which we think closely resembles the metastatic setting.

Endocrine treatment of advanced breast cancer
Mitchell Dowsett

Endocrine treatment is the preferred first-line therapy for advanced breast cancer because of its good tolerability. There are several groups of agents which differ in their mode of action but almost all in some way reduce stimulation by oestrogen. Over recent years, there has been a substantial increase in the number of medical agents in clinical trial. New antioestrogens with reduced or no agonist activity, and potent, more specific, aromatase inhibitors are now reaching the clinic. In most cases, the clinical effectiveness of these agents remains to be fully established and their optimal therapeutic application is yet to be determined.

Rationale for the use of bisphosphonates in breast cancer
John A. Kanis

The variability of different breast cancers in the susceptibility to metastatic bone disease is poorly understood. Factors that determine the viability of metastatic cells are also poorly understood, but may depend in part upon gene expression of PTHrP and the vitamin D receptor. In contrast, much more is known of the manner in which metastatic breast disease affects bone remodelling to induce osteolytic bone disease. Mechanisms include a generalized increase in activation frequency at sites close to metastatic tissue, an imbalance between the amount of bone formed and that resorbed within resorption cavities, and uncoupling of bone formation from bone resorption. The greatest morbidity from metastatic bone disease arises from osteolytic disease and gives rise to hypercalcaemia, bone pain and fractures. Since osteolysis is primarily mediated by the activation of osteoclasts, there has been a great deal of interest in the use of agents which primarily affect bone metabolism to alter the natural history of metastatic bone disease. Non-steroidal anti-inflammatory agents and cytotoxic agents are capable of inducing responses in bone, but are limited by their toxicity when effective doses are utilized. The use of calcitonin in the long-term suppression of osteolysis has also been disappointing. The bisphosphonates are, however, capable of inducing sustained decreases in osteoclast activity and numbers in patients with osteolytic bone disease. There are now several studies which have examined the effects of the bisphosphonates on skeletal morbidity in breast cancer. Both clodronate and pamidronate decrease the incidence of hypercalcaemia, bone pain and pathological fractures, but do not significantly alter mortality. Given, however, the unchanging survival in patients with metastatic bone disease, significant improvements in the quality of remaining life is an important therapeutic effect.

Proper sequence of endocrine therapies in advanced breast cancer
Carsten Rose

Tamoxifen (TAM) is widely used as therapy in early cancer and first-line endocrine therapy in metastatic disease. Despite this therapy, many patients relapse and an important question is: What is the preferred sequence of endocrine therapies in metastatic breast cancer (MBC). While treatment with oophorectomy, aminoglutethimide or progestins have been a logical choice after failure to Tamoxifen recent research has extended the options for endocrine therapy of MBC. New selective aromatase inhibitors (AI) are now in clinical use. The first commercially available of these inhibitors is LENTARON®. The active ingredient of LENTARON is a steroidal compound 4-OH-androstenedione: Formestane. It is presented as a depot formulation and applied as an i.m. injection of 250 mg every second week. Previous findings from phase II trials have indicated similar activity as other endocrine treatmentmodalities. Clinical investigations in properly conducted phase III trials have revealed that the efficacy of LENTARON® matches the results which can be obtained with TAM and Megace® in trials of first and second-line endocrine therapy. Fifty-four and 51% of MBC patients, respectively, did benefit from therapy with LENTARON® in these phase III trials by achieving objective responses or stable disease. Moreover, similar overall survival was seen. The systemic tolerability of LENTARON® is comparable to that of TAM, and LENTARON® seems less systemically toxic than Megace®. Local side effects occurred in approximately 7% of the patients giving rise mainly to pain or inflammation at the injection site. In elderly patients, LENTARON® therapy assures compliance and no interference with other oral medications has been observed. In conclusion, since the endocrine treatment modalities are comparable in terms of efficacy the optimal sequence of these treatments is based upon differences in tolerability. Patients previously treated with Tamoxifen and with a high probability of a further endocrine response could preferably be treated with a selective AI like LENTARON® as second-line endocrine therapy followed by a progestin upon progression in responders.

Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update
R.M. Clark, T. Whelan, M. Levine, R. Roberts, A. Willan, P. McCulloch, M. Lipa, R.H. Wilkinson, L.J. Mahoney*
For the Ontario Clinical Oncology Group

Background: Breast-conservation surgery is now commonly used to treat breast cancer. Postoperative breast irradiation reduces cancer recurrence in the breast. There is still controversy concerning the necessity of irradiation of the breast in all patients. Purpose: We present an update of results from a randomized clinical trial designed to examine the efficacy of breast irradiation following conservation surgery in the treatment of women with axillary lymph node-negative breast cancer. The patients were enrolled from April 1984 through February 1989. Initial results were published in 1992 after a median follow-up time of 43 months. It was reported that recurrence of cancer in the breast occurred in 5.5% of the patients who received breast irradiation compared with 25.7% of those who did not. No difference in survival was detected between the two treatment groups. Now that the median patient follow-up has reached 7.6 years, the trial end points have been re-examined and an attempt has again been made to identify a group of patients at low risk for recurrence of cancer in the breast. Methods: Eight hundred thirty-seven patients with node-negative breast cancer were randomly assigned to receive either radiation therapy (n = 416) or no radiation therapy (n = 421) following lumpectomy and axillary lymph node dissection. The cumulative local recurrence rate as a first event, distant recurrence (i.e., occurrence of metastasis) rate, and overall mortality rate for the treatment groups were described by he Kaplan-Meier method and compared with the use of the logrank test. The Cox proportional hazards model was used to adjust the observed treatment effect for the influence of various prognostic factors (patient age, tumor size, estrogen receptor level, and tumor histology) at study entry on the outcomes of local breast recurrence, distant recurrence, and overall mortality. All P values resulted from the use of two-tailed statistical tests. Results: One hundred forty-eight (35%) of the nonirradiated patients and 47 (11%) of the irradiated patients developed recurrent cancer in the breast relative risk for patients in the former versus the latter group = 4.0; 95% confidence interval = 2.83-5.65; P < 0.0001). Ninety-nine (24%) of the patients in the former group have lied compared with 87 (21%) in the latter group. Age (< 50 years), tumor size (> 2 cm), and tumor nuclear grade (poor) continued to be important predictors for local breast relapse. On the basis of these factors, we were unable to identify a subgroup of patients with a very low risk for local breast cancer recurrence. Tumor nuclear grade, as previously reported, and tumor size were important predictors for mortality. Conclusions: Breast irradiation was shown to reduce cancer recurrence in the breast, but there was no statistically significant reduction in mortality. A subgroup of patients with a very low risk for local breast recurrence who might not require radiation therapy was not identified.

Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer
Douglass C. Tormey, Robert Gray, Hendre C. Falkson*
For the Eastern Cooperative Oncology Group

Background: Data from a pilot study published in 1984 suggested that tamoxifen administration (as adjuvant hormonal therapy) for more than 5 years after initial breast cancer surgery might have therapeutic benefit. Purpose: A randomized trial was performed to assess the efficacy of maintaining tamoxifen therapy beyond 5 years in women with axillary lymph node-positive breast cancer who had been treated with surgery followed by 1 year of chemotherapy and 5 years of tamoxifen. Methods: One hundred ninety-four women (87 postmenopausal and 107 premenopausal) enrolled in two concurrent Eastern Cooperative Oncology Group adjuvant trials (E4181 for postmenopausal patients and E5181 for premenopausal patients) were randomly assigned to continued tamoxifen therapy or observation. Data for 193 women (87 postmenopausal and 106 premenopausal) were available for analysis. Median follow-up is 5.6 years since the randomization at 5 years, with the longest follow-up being 8.0 years. The major analyses measured events from the time of randomization until relapse or death; these included time-to-relapse analyses, with new opposite-breast cancers counted as treatment failures, and survival analyses. Time-to-relapse comparisons and survival comparisons for women in the two treatment groups were made by use of the Kaplan-Meier method and the logrank test. Reported P values are two-sided. Results: Five years after the randomization, no statistically significant differences were noted in either time to relapse or survival between women continuing to receive tamoxifen and those on observation. Eighty-five percent of the women receiving tamoxifen were disease free at this time compared with 73% of those on observation (P = 0.10); survival was 86% for those continuing to receive tamoxifen and 89% for those on observation (P = 0.52). Differences in the time to relapse and survival between premenopausal and postmenopausal women assigned to the two treatment groups were also not statistically significant (time to relapse: P = 0.38 and P = 0.16 for premenopausal and postmenopausal patients, respectively; survival: P = 0.18 and P = 0.72 for premenopausal and postmenopausal patients, respectively). There was an indication that women with estrogen receptor-positive tumors may experience a longer time to relapse with continued tamoxifen therapy (P = 0.014); however, the survival difference for this subgroup was not statistically significant (P = 0.81). The toxicity patterns in the two treatment groups were similar. Conclusions and Implications: Our results suggest that further evaluation of adjuvant tamoxifen therapy beyond 5 years in women with axillary lymph node-positive, estrogen receptor-positive breast cancer who have also been treated with adjuvant chemotherapy would be appropriate.

Factors influencing the distribution of metastases and survival in metastatic breast carcinoma
Ibrahim Barista, M.D., Esmen Baltali, M.D., Ibrahim H. Güllü, M.D., Nilüfer Güler, M.D., Ismail Çelik, M.D. Osman Saraçbasi, Ph.D., Gülten Tekuzman, M.D., Ayse Kars, M.D. Yavuz Özisik, M.D., Sevket Ruacan, M.D., I. Late Atahan, M.D., and Dinçer Firat, M.D.

A total of 370 patients with metastatic breast carcinoma who had been followed at Hacettepe Oncology Department between 1980 and 1991 were retrospectively analyzed for the factors influencing the distribution of metastases and survival. Median age was 47 years. Radical or modified radical mastectomies were performed in 199 (53.8%). Infiltrative ductal carcinoma was the most common pathologic subtype (69.4%). In 191 patients who were evaluated for estrogen receptor (ER) status, 101 (52.9%) were positive and 90 (47.1%) were negative. The distribution of first metastases did not differ between the soft tissue, bone, and visceral sites. The second, third, and fourth metastases were more common in visceral sites (p < 0.05). ER and menopausal status did not affect distribution. Mortality rate was significantly lower in the group having the first metastasis to the bone (p < 0.05). Of interest, first metastases were predominantly found in visceral sites in patients having radical or modified radical mastectomies (p < 0.05). Response to therapy, presence of initial metastases, axillary status, and age were the important factors influencing the overal survival in univariate analysis, whereas response to therapy, ER status, age, and presence of initial metastases were the important factors according to the multivariate analysis.

Surgical therapy of primary cutaneous melanoma
Patrick J. Geraghty, M.D., Timothy M. Johnson, M.D., Vernon K. Sondak, M.D. and Alfred E. Chang, M.D.
From the Department of Surgery (P.J.G., V.K.S., A.E.C.) and Department of Dermatology (T.M.J.), University of Michigan Medical Center, Ann Arbor, Michigan

This review focuses on the surgical treatment of primary cutaneous melanoma. Interpretation of biopsy results and a rational approach to preoperative screening methods for metastases are examined. The marked changes in operative approach to melanoma over the past century are reviewed, with emphasis on the impact of prospective, randomized trials upon the width of surgical margins for melanoma. General principles of current surgical technique are discussed, with attention given to modifications of technique dictated by unique anatomic tumor sites.

Screening for cutaneous melanoma by skin self-examination
Marianne Berwick, Colin B. Begg, Judith A. Fine, George C. Roush, Raymond L. Barnhill*

Background: Although some evidence indicates that early detection protects against the development of lethal melanoma, no randomized clinical trials have been conducted to measure the efficacy of early detection (or screening) in preventing death from this disease. Since melanoma incidence in the United States is relatively rare, a randomized clinical trial to test the efficacy of screening would be extremely expensive. Purpose: As an alternative to a randomized clinical trial, we conducted a population-based, case-control study to investigate whether early detection through skin self-examination (SSE) is associated with a decreased risk of lethal melanoma (includes the presence of advanced disease with distant metastases in addition to death from melanoma). Methods: SSE (conducting a careful, deliberate, and purposeful examination of the skin) was assessed in all subjects by use of a structured questionnaire and personal interviews. The major exposure variable, SSE, was defined following focus-group interviews with melanoma patients and healthy control subjects. The final study population consisted of 1199 Caucasian residents of the state of Connecticut enrolled from January 15, 1987, through May 15, 1989; 650 individuals were newly diagnosed with cutaneous melanoma, and the remaining 549 individuals were age- and sex-frequency matched control subjects from the general population. During the study interviews, nevi on the arms and backs of subjects were counted. In 5 years of follow-up (through March 1994), 110 lethal cases of melanoma were identified. The study design allowed separate estimation of the impact of SSE on reduced melanoma incidence (primary prevention) and survival among incident cases (secondary prevention). Odds ratios (ORs) were used to measure the associations between SSE and melanoma and between SSE and lethal melanoma. Results: SSE, practiced by only 15% of all subjects, was associated with a reduced risk of melanoma incidence (adjusted OR = 0.66; 95% confidence interval [CI] = 0.44-0.99; comparing case patients with control subjects). The data indicated further that SSE may reduce the risk of advanced disease among melanoma patients (unadjusted risk ratio = 0.58; 95% CI = 0.31-1.11); however, longer follow-up is required to confirm this latter estimate. If both estimates are correct, they suggest, in combination, that SSE may reduce mortality from melanoma by 63% (adjusted OR = 0.37; 95% CI = 0.16-0.84; comparing lethal cases with general population controls). Conclusions and Implications: SSE may provide a useful and inexpensive screening method to reduce the incidence of melanoma. SSE may also reduce the development of advanced disease. The results of this study need to be replicated before strategies to increase the practice of SSE are further developed and promoted.

The management of retroperitoneal soft tissue sarcomas
M.P. Jenkins, J.C. Alvaranga and J.M. Thomas
Soft Tissue Sarcoma Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, U.K.

Over a 5-year period, all retroperitoneal soft tissue sarcomas (119) referred to the Royal Marsden Hospital, London, U.K., were recorded prospectively on a database and managed with a consistent treatment policy. On multivariate analysis, the significant factors responsible for determining prognosis were grade and completeness of excision. Despite improvements in surgical clearance rates (nearly 50% completely excised in this series), the prognosis was poor with 2- and 5-year survival rates of 53 and 20%, respectively. Further improvements in survival rates will depend on better adjuvant treatment.

The relationship between postoperative decline of serum CA 125 levels and size of residual disease after initial surgery in patients with advanced ovarian cancer: A CTF study
Angiolo Gadducci, Fabio Landoni, Tiziano Maggino, Enrico Sartori, Paolo Zola, and Antonio Fanucchi

This retrospective study assessed 46 patients with advanced ovarian cancer who had elevated preoperative serum CA 125 (> 35 U/ml) and who had another serum CA 125 assay 6-9 days after surgery. Preoperative CA 125 levels were similar in patients with residual disease below 20 mm and in those with larger residuum. The postoperative decline of serum CA 125 was significantly higher in patients with small residual disease at any preoperative serum CA 125 value. By taking 60% as the cutoff of CA 125 decline, the diagnostic accuracy of this parameter in discriminating between patients with residual disease below or above 20 mm improved progressively when we considered patients with increasing preoperative antigen values. However, even in the subset of patients with preoperative serum CA 125 above 400 U/ml, 2 of the 20 patients with less than 20 mm residual disease had a percentage reduction of antigen levels lower than 60%, whereas 5 of the 10 patients with larger than 20 mm residuum had a CA 125 decline higher than 60%. Therefore, we believe that the perioperative changes of CA 125 levels have a limited clinical relevance in the management of patients with ovarian cancer.

Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study
Ian J. Jacobs, Steven Skates, Ann Prys Davies, Robert P Woolas, Arjun Jeyerajah, Pru Weidemann, Karen Sibley, David H. Oram

Objective - To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women.
Design - Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration ³ 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire.
Setting - General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital.
Subjects - 22,000 volunteers, all postmenopausal women ³ 45 years of age; recruited between 1 June 1986 and 1 May 1990.
Intervention - Surgical investigation if the ultrasound examination was abnormal.
Main outcome measures - Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result.
Results - 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration ³ 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration ³ 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration ³ 100 U/ml.
Conclusion - CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women.

Genetic, biochemical, and multimodal approaches to screening for ovarian cancer
Ian Jacobs, M.A., M.D., MRCOG
CRC Human Cancer Genetics Research Group, University of Cambridge and Department of Gynaecological Oncology, The Royal London Hospital, London, United Kingdom

The correlation between 5-year survival rates for ovarian cancer and stage at diagnosis has long suggested that early detection by screening may improve the prognosis for the disease. This hypothesis has not yet been tested in a randomized controlled study and all evidence concerning the efficacy of potential screening tests is indirect. The role of ultrasonography and other imaging techniques such as Doppler color flow in screening for ovarian cancer is considered in other contributions to this publication. This paper will focus briefly on the role of genetic markers in the selection of a target population for screening and discuss the role of tumor markers used alone or as part of a multimodal approach to screen for ovarian cancer.

Estrogen replacement therapy and risk of epithelial ovarian cancer
Harvey A. Risch, M.D., Ph.D.
Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, Connecticut 06510

Estrogen replacement therapy (ERT), in common use among menopausal women, has been inconsistently related to risk of ovarian cancer. Part of the inconsistency may be due to differences in risk according to tumor histology. We therefore compared, within histologic groups, 367 cases of invasive epithelial ovarian cancer to 564 population controls on history of ERT practices. In multivariate logistic regression analyses adjusted for age, parity, oral-contraceptive usage, and other factors, the relative odds of nonmucinous ovarian cancer increased by 5.1% for each year of ERT use [i.e., adjusted odds ratio, 1.051; 95% confidence interval (CI), 1.01 - 1.09, as multiplicative factor for each year of use]. In particular, compared to never use, women who employed ERT for a total of 5 years or longer had a relative odds of 2.03 (95% CI, 1.04-3.97) of having a serous carcinoma and 2.81 (95% CI, 1.15-6.89) of having an endometrioid carcinoma. Mucinous tumors were not associated with use. ERT usage may contribute to the development of nonmucinous types of ovarian cancer, and additional histology-specific analysis of this association in other studies is warranted.

Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography
Ian Jacobs, Ann Prys Davies, Jane Bridges, Isabel Stabile, Toby Fay, Adrian Lower, J.G. Grudzinskas, David Oram

Objective - To assess the performance of the sequential combination of serum CA 125 measurement and ultrasonography in screening for ovarian cancer.
Design - The serum CA 125 concentration of each subject was determined and those with a concentration ³ 30 U/ml were recalled for abdominal ultrasonography. If ultarsonography gave abnormal results surgical investigation was arranged. Volunteers were followed up by annual postal questionnaire.
Setting - General practice, occupational health departments, ovarian cancer screening clinic.
Subjects - 22,000 women volunteers who were postmenopausal and aged over 45 years.
Main outcome measures - Apparent sensitivity, specificity, positive predictive value, years of cancer detected.
Results - 41 women had a positive screening result and were investigated surgically. 11 had ovarian cancer (true positive result) and 30 had other disorders or no abnormality (false positive result). Of the 21,959 volunteers with a negative screening result, eight subsequently presented clinically with ovarian cancer (false negative result) and 21,951 had nor developed ovarian cancer during follow up (apparent true negative result). The screening protocol achieved a specificity of 99.9%, a positive predictive value of 26.8%, and an apparent sensitivity of 78.6% and 57.9% at one-year and two-year follow up respectively. The estimated number of years of cancer detected by the prevalence screen was 1.4 years.
Conclusions - This screening protocol is highly specific for ovarian cancer and can detect a substantial proportion of cases at a preclinical stage. Further investigation is required to determine the effect of the screening protocol on the ratio of early to late stage disease detected and on mortality from ovarian cancer.

Treatment results of nasopharyngeal cancer. A nationwide survey from Finland
Mikael Kajanti, Martti Flander, Reidar Grennan, Tenho Hietanen, Maija Romppanen, Marita Turunen, Ritva Valavaara and Heikki Joensuu

The nationwide experience of treating nasopharyngeal cancer in Finland during the period 1980-1989 was reviewed. Of the 107 patients included in the present analysis, 13 were treated palliatively only, and three had metastatic disease at their first clinical presentation, whereas the rest (n = 91) were treated with radical radiotherapy, of whom, 8 patients received adjuvant chemotherapy after radiotherapy. The 5-year actuarial survival rates of these 91 patients was 52%, and by the UICC stage they were classified as follows: stage I 75% (n = 12), stage II 60% (n = 5), stage III 59% (n = 34), and stage IV 38% (n = 40). According to the Cox’s stepwise proportional hazard model the most important factors influencing favourable survival were the total dose of radiotherapy expressed in terms of Biologically Effective Dose (BED) with a time factor, a small size of the primary tumour and a high performance status according to the WHO scale, whereas the most important factors influencing the local control analysis were the total dose of radiotherapy (expressed in BED) and the cervical lymph node status.

Evaluation of patients with advanced neuroblastoma surviving more than 5 years after initiation of an intensive Japanese protocol: a report from the study group of Japan for treatment of advanced neuroblastoma
Makoto Iwafuchi, M.D., Jiro Utsumi, M.D., Yoshiaki Tsuchida, M.D., Michio Kaneko, M.D., Shiro Matsuyama, M.D., Naomi Ohnuma, M.D., Nobuyuki Taguchi, M.D., Hideo Mugishima, M.D., Jotaro Yokoyama, M.D., Shingi Sasaki, M.D. Akira Yoshioka, M.D., Noboru Nagahara, M.D., Masahiro Fukuzawa, M.D. and Sachiyo Suita, M.D.

In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate.
Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward.

Histological analysis of aggressiveness and responsiveness in Wilm’s tumor
J. Bruce Beckwith, M.D., Craig E. Zuppan, M.D., Nancy G. Browning, M.S., Jami Moksness, B.S. and Norman E. Breslow, PhD

The clinical behavior and outcome for any neoplasm are determined originally by its aggressiveness. As adjuvant therapy becomes increasingly effective for that neoplasm, responsiveness to therapy assumes a larger role in determining outcome. Wilms’tumor (WT) provides instructive examples of the dissociation of aggressiveness from responsiveness. The presence of gigantic nuclei with multipolar mitotic figures (anaplasia) appears to be a marker of resistance to therapy, but not of increased aggressiveness. For this reason, anaplasia in a stage I WT and anaplasia confined to discrete foci within the primary tumor have no adverse prognostic significance following surgical resection. The prognostic significance of anaplasia is apparently limited to those patients in whom anaplastic cells remain following atempted surgical resection.
WT with predominantly epithelial differentiation usually have a low degree of aggressiveness. In this study, 81.3% of WT with this pattern were stage I. This feature accounts for the high cure rate associated with this pattern prior to the advent of effective adjuvant therapy. However, epithelial predominant WT that present with advanced stage disease may be quite resistant to therapy, with relapse and death rates higher than for more aggressive WT patterns. In contrast, the diffuse blastemal pattern is associated with marked aggressiveness, but with high survival rates suggesting it is usually responsive to current therapy. These features illustrate the independence of aggressiveness and responsiveness in determining outcome for some patients with cancer. Grading systems must be reevaluated with each significant change in therapy. In order to formulate rational therapy, it is important to determine whether prognostic markers are associated with aggressiveness or responsiveness.

Management of cancer of the prostate
William J. Catalona, M.D.

Prostate cancer is the second leading cause of death from cancer among men; 25 percent of men with prostate cancer die of the disease1. Moreover, many patients who do not die of prostate cancer require treatment to ameliorate symptoms such as pain, bleeding, and urinary obstruction. Thus, prostate cancer is also a major cause of suffering and of health care expenditures.
The high rate of mortality from prostate cancer may be due to late detection. In recent studies, screening for prostate cancer has combined the measurement of serum prostate-specific antigen (PSA) - the most accurate single test for the detection of prostate cancer - with the more traditional approach of digital rectal examination. As compared with other diagnostic approaches, these two procedures, in conjunction with ultrasound-guided biopsy of the prostate, increase the overall rate of cancer detection by 70 percent, double the detection rate for organ-confined cancers, and avoid detection of most medically unimportant cancers (only 7 percent of detected cancers are microfocal and low in grade)2-4. The National Cancer Institute has initiated a large trial to determine whether screening for prostate cancer with serum PSA measurements and digital rectal examination will reduce morbidity and mortality, but this study will take several years to complete.
The American Cancer Society and the American Urological Association recommend that men who are 50 years of age or older undergo annual measurement of serum PSA and rectal examination for early detection of prostate cancer and that men at high risk for prostate cancer, such as blacks and those with a strong family history, undergo annual screening starting at the of 40 years. Although there is uncertainty about the natural history of the cancers detected by screening, the available evidence suggests that most are clinically important4. Because treatment in the early stages of cancer is less costly than treatment in advanced stages, early detection with the use of these two procedures may be cost effective5, 6.

A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with ‘good-risk’ metastatic non-seminomatous germ cell tumors
C. Bokemeyer¹, O. Köhrmann², J. Tischler³, L. Weißbach⁴, U. Räth⁵, A. Haupt¹, P. Schöffski⁶, A. Harstrick⁷ & H.-J. Schmoll^{8 1}Department of Internal Medicine, University of Tübingen, Tübingen; ²Department of Urology, Städtisches Klinikum Mannheim, Mannheim; ³Department of Hematology/Oncology, Klinikum Minden, Minden; ⁴Department of Urology, Krankenhaus Am Urban, Berlin; ⁵Department of Hematology/Oncology, University of Heidelberg; ⁶Department of Hematology/Oncology, Hannover University Medical School, Hannover; ⁷Department of Oncology, West-German Cancer Center, Essen; ⁸Department of Hematology/Oncology, University of Halle, Halle, Germany

Background: Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with ‘minimal’- and ‘moderate-disease’ non-seminomatous germ cell tumors, according to the Indiana University classification.
Patients and methods: PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers.
Results: No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEB in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from the disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patients, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03).
Conclusion: This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with "good-risk" non-seminomatous germ cell tumors.

Objective - To determine for the first 4 years of serial prostate-specific antigen (PSA) - based screening trends in compliance, prevalence of abnormal screening test results, cancer detection rates, and stage and grade of cancers detected.
Design - A community-based study of serial screening for prostate cancer with serum PSA measurements.
Setting - University medical center.
Subjects - A total of 10,248 male volunteers at least 50 years old who were screened at 6-month intervals for a minimum of 48 months.
Main Outcome Measures - The proportion of men who returned for serial screening, the proportion with elevated PSA levels, the proportion with newly elevated PSA levels, prostate cancer detection rates, and the distribution of tumor stages and grades at diagnosis.
Results - At 48 months, 79% of volunteers returned for screening. During this interval there was a decrease in the proportion of volunteers with serum PSA levels higher than 4.0 ng/mL (from 10% to 6%-7%), in cancer detection rates (from 3% to < 1%), and in the proportion with clinically advanced cancer (from 6% to 2%). In men who underwent surgery, the proportion with high-grade cancer decreased (from 11% to 6%), and the proportion with pathologically advanced cancer was proportionately reduced but not significantly reduced (from 33% to 27%).
Conclusions - With serial PSA-based screening, the proportion of men with abnormal test results decreased, and the prostate cancer detection rate decreased to near the reported population-based incidence rate. There was also a shift to detection of cancers at an earlier clinical stage and detection of lower-grade cancers. If PSA screening is ultimately shown to be beneficial, then appropriate cost-benefit analyses will be required to determine how the shifts in cancer detection rate and cancer stage will affect the economics of serial PSA-based screening.

Flutamide withdrawal and concomitant initiation of aminoglutethimide in patients with hormone refractory prostate cancer

Total androgen deprivation is by many clinicians considered to be the optimal therapeutic regimen for hormone sensitive prostate cancer (1-2). Complete androgen blockade is usually accomplished with either orchiectomy or an LHRH agonist such as leuprolide, that inhibits testicular androgen production, together with an antiandrogen such as flutamide. Flutamide is a pure antiandrogenic compound that prevents the androgen receptor from binding testosterone and dihydrotestosterone (DHT) without exhibiting hormonal activity of its own (3, 4).
Once disease ceases to respond to initial hormonal therapy, it is classified as hormone-refractory. Therapeutic intervention in this patient population is primarily palliative, with no therapy demonstrating a clear survival benefit. The withdrawal of flutamide is a documented maneuver having activity in hormone-refractory prostate cancer (HRPC) (29-33% response rates) (5, 6). In vitro data suggest that a mutant androgen receptor may be responsible for this withdrawal phenomenon (7-12). The hormone sensitive prostate cancer cell line LNCaP express a mutant androgen receptor which recognizes flutamide, as well as androgenic steroids, estradiol, progesterone, and DHT, as agonists (9-11). An identical androgen receptor mutation has been isolated from patients with HRPC (7, 8, 12).
Aminoglutethimide partially inhibits the synthesis of the steroids testosterone, DHT, progesterone, and estradiol by inhibiting the activity of the enzyme aromatase as well as the conversion of cholesterol to 20a-hydroxycholesterol, the first reaction of steroidogenesis from cholesterol (13). We hypothesized that if patients with HRPC express a mutant receptor similar to that found in the LNCaP cell line then the addition of aminoglutethimide would potentially enhance the flutamide withdrawal phenomenon. This report analyzes the effect of aminoglutethimide administration on the flutamide withdrawal in a small population of patients with HRPC who progressed after initial treatment with combined androgen blockade, suramin, and hydrocortisone.

Utilidad de la radioterapia en los linfomas no-Hodgkin
M. de las Heras, J. Salinas, J. Fernández

La radioterapia es un tratamiento muy útil en los linfomas no-Hodgkin, aunque debido a la hetrogeneidad de estas neoplasias, a los diferentes comportamientos en la clínica, y a las terapéuticas disponibles en la actualidad, sus indicaciones no están bien establecidas. La interación de la quimioterapia y radioterapia, los dos tratamientos más utilizados en estas enfermedades, necesita una mayor coordinación como ocurre en la enfermedad de Hodgkin.

Lymphoma classification - The gap between biology and clinical management is closing
By Wolfgang Hiddemann, Dan L. Longo, Bertrand Coiffier, Richard I. Fisher, Fernando Cabanillas, Franco Cavalli, Lee M. Nadler, Vincent T. De Vita, T. Andrew Lister, and James O. Armitage

New Insights into the pathogenesis of lymphoid malignancies have been gained by novel techniques such as genetic, molecular, and immunologic methods and have not only broadened our knowledge about the origin and development of malignant lymphomas, but also have substantial clinical implications. Hence, distinct disorders can be defined more precisely and therapeutic strategies may be directed more specifically to well-defined lymphoma entities. The closing gap between a better understanding of lymphoma biology and its translation into the clinical management of lymphoid malignancies requires an appropriate adaptation of histopathologic classification and clinical grouping and stimulates the reflection and reassessment of previously developed and newly proposed classification systems.
Over the past 40 years, the challenge of adaptation to new knowledge and novel techniques has reappeared several times and has prompted reconsideration of the classification and clinical grouping of malignant lymphomas from time to time. The process of reconsideration has regularly followed a sequence of steps which comprise the proposal of a new classification, its evaluation and testing, its acceptance and broad application or rejection, respectively, and finally its revision and modification as new information is gained (Fig. 1).
Two years ago, a new histopathologic classification for neoplasms of the lymphoid lineage was proposed by the International Lymphoma Study Group1. It emerged from the joint efforts of an international group of pathologists who tried to adapt the categorization of malignant lymphomas to the present status of knowledge and techniques. The first step of a new classification system was, therefore, signaled by the appearance of the “Revised European American Lymphoma” schema which has now entered the subsequent stages of evaluation and testing2. At the second anniversary of its publication in Blood, it seems appropriate to consider the general concept of the “Revised European American Lymphoma” calssification, its potential clinical application and perspective, as well as its differences from preceding groupings.

Splenectomy for non-Hodgkin’s lymphoma
Jeffrey Brodsky, M.D., Antoine Abcar, B.S., and Michael Styler, M.D.

Splenomegaly is a common occurrence in the course of non-Hodgkin’s lymphoma (NHL), sometimes leading to development of bulk symptoms or cytopenias. Splenomegaly may also be the primary manifestation of NHL. We reviewed our experience with diagnostic and therapeutic splenectomy for NHL over the past 3 years. In July of 1991, a prospective database had been established to evaluate elective splenectomy for hematologic disease; of 58 patients, 12 had NHL. Splenectomy was performed for diagnostic purposes, correction of cytopenias, and relief of bulk symptoms. Most patients had more than one indication for splenectomy. Operative hemorrhage requiring transfusion was seen only in patients with massive splenomegaly (> 1,500 g). Median postoperative hospital stay was 4 days. There was no operative mortality or major morbidity. Minor morbidity was seen in 17% of patients. A favorable hematologic response was seen in 80% of cytopenias at the 3-month postoperative interval. Splenectomy is safe and effective in appropriately selected patients with NHL.

Mycosis fungoides and Sézary syndrome
By Eleni Diamandidou, Philip R. Cohen, and Razelle Kurzrock

Mycosis fungoides (MF) is an uncommon, indolent T-cell lymphoma first described by Alibert1 in the early 1800s. It primarily involves the skin at early stages of the disease, with plaques being the typical feature. After a variable period of time, it may progress with development of cutaneous tumors and spread to visceral sites and lymph nodes (LNs)2. Sézary syndrome (SS) is an erythrodermic variant of MF (MF) associated with the presence of circulating tumor cells in the peripheral blood.
Although MF/SS are often called cutaneous T-cell lymphomas (CTCLs) they should be differentiated from other non-Hodgkin’s lymphomas that involve the skin such as peripheral T-cell lymphomas and adult T-cell leukemia/lymphomas. The diagnosis of MF rests on the clinical presentation as well as the histopathologic findings of an epidermotropic lymphoma with light microscopy showing a dermal infiltrate of lymphocytes with hyperconvoluted cerebriform nuclei and Pautrier’s microabscesses. The malignant cells usually have a mature CD4+ T-helper cell phenotype. Because of the heterogeneity of both clinical and pathologic patterns, the diagnosis of MF is often difficult to make.

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group
By Nancy Lee Harris, Elaine S. Jaffe, Harald Stein, Peter M. Banks, John K.C. Chan, Michael L. Cleary, Georges Delsol, Christine De Wolf-Peeters, Brunangelo Falini, Kevin C. Gatter, Thomas M. Grogan, Peter G. Isaacson, Daniel M. Knowles, David Y. Mason, Hans-Konrad Muller-Hermelink, Stefano A. Pileri, Miguel A. Piris, Elisabeth Ralfkiaer, and Roger A. Warnke

The histologic categorization of lymphoma has been a source of frustration for many years for both clinicians and pathologists. In the last 10 years, much new information has become available about the lymphomas, resulting in recognition of new entities and refinement of previously recognized disease categories, raising the question of whether it is time for a new lymphoma classification. In this paper we report the result of an international review of lymphomas, which we hope may clarify some of the confusion surrounding this topic.
This review was conducted at a meeting of 19 hematopathologists with particular interest and experience in lymphomas (the International Lymphoma Study Group) in Berlin, Germany, in April 1993. At previous meetings in Europe and the United States, we had come to believe that, despite the variety of classification schemes used, many hematopathologists appeared to agree on a rather large number of distinct lymphoma entities that they recognize and diagnose in daily practice. We believed that we could provide a useful service to both pathologists and clinicians struggling with the classification of lymphomas by attempting to arrive at a consensus regarding the categories of lymphoid neoplasia that can be reliably recognized at present.
What emerged from this meeting was, first, that each of us had independently evolved ways of viewing these diseases that were essentially identical. Surprisingly, there was little divergence between European and US participants. Second, it was evident that, while many of these lymphoma entities are recognized in the Kiel Classification1-6, the Lukes-Collins Classification7, and the Working Formulation8, they often go by different names in different publications and may have variable criteria for diagnosis9. Furthermore, we found that many of us had doubts about both the practical feasibility and the scientific validity of distinguishing certain subtypes in these systems. We also found that while some lymphoma categories are easy to recognize, others are disturbingly prone to subjective variability. This feature of lymphoma diagnosis has not been emphasized in previous schemes for classification, which imply that all categories are equally easy for the pathologist to recognize.
Ideally lymphomas, like most other tumors, should be classified according to their presumed normal counterpart, to the extent possible. This should provide the best information about disease biology, natural history, and response to treatment. However, despite extensive study, the definition of lymphoid compartments in humans and movement of cells between these compartments still contains many uncertainties. Furthermore, there are difficulties in defining the full extent of the neoplastic clone in individual cases of lymphoma, and some well-defined lymphoma types lack obvious normal counterparts. Consequently, although differentiation schemes provide useful conceptual frameworks for understanding lymphomas and suggest important new lines of research, our current understanding of both the immune system and the lymphomas appears to be inadequate to support a biologically “correct” lymphoma classification. Thus, a classification strictly based on a theoretical relationship of tumors to normal stages of differentiation is both unrealistic and unnecessary for the practical categorization of human lymphomas.

Electron beam treatment for cutaneous T-cell lymphoma
Glenn W. Jones, BSc, M.D., FRCPC, Richard T. Hoppe, M.D., and Eli Glatstein, M.D.

This article reviews total skin electron radiation (TSE) as a treatment for mycosis fungoides and the Sézary syndrome (MF). Previous summaries have provided only reviews of radiation techniques12, 32, or qualitative descriptions of but a portion of published clinical data14. The goals of this article are (1) to critically describe the technique, (2) to provide better estimates of the effectiveness of TSE, and (3) to suggest some research questions.

Intrinsic and acquired resistance to methotrexate in acute leukemia
Richard Gorlick, M.D., Erdem Goker, M.D., Tanya Trippett, M.D., Mark Waltham, Ph.D., Debabrata Banerjee, Ph.D., and Joseph R. Bertino, M.D.

Methotrexate, a folic acid antagonist, is used extensively not only for the treatment of cancer but also for the treatment of rheumatoid arthritis, and autoimmune disease and for the prevention of graft-versos-host disease after transplantation. The drug is also used as abortifacient1, 2. Other folate antagonists are used to treat bacterial infection (trimethoprim),malaria (pyrimethamine), and Pneumocystis carinii infection (trimetrexate with leucovorin)3, 4. As with other drugs used to treat infectious diseases or cancers, the development of resistance limits the effectiveness of these folate antagonists. An understanding of the mechanisms of resistance to this class of drugs is important for their optimal use, as well as for the development of new drugs.
The recent application of new and sensitive molecular biologic techniques has made it possible to study the genetic alterations underlying the phenotypic................associated.with aquired resistance to methotrexate in tumor tissue. Methotrexate is an important component of the treatment of acute lymphocytic leukemia, which can be cured in about 70 percent of children5, 6. The mechanisms of acquired resistance to the drug have been studied in patients with relapses of acute lymphocytic leukemia. In contrast, methotrexate is ineffective in the treatment of acute myelocytic leukemia, and mechanisms of intrinsic resistance to the drug have been examined in patients with this type of leukemia. Here, we review the current understanding of resistance to methotrexate in patients with leukemia. The drug’s mechanisms of action and its therapeutic use are reviewed in detail elsewhere7, 9.

Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia
By Sadahiro Tamiya, Masao Matsuoka, Ken-ichiro Etoh, Toshiki Watanabe, Shimeru Kamihira, Kazunari Yamaguchi, and Kiyoshi Takatsuki

Adult T-cell leukemia (ATL), an aggressive neoplasm of mature helper T cells, is etiologically linked with human T lymphotropic virus type I (HTLV-I). After infection, HTLV-I randomly integrates its provirus into chromosomal DNA. Since ATL is the clonal proliferation of HTLV-I-infected T lymphocytes, molecular methods facilitate the detection of clonal integration of HTLV-I provirus in ATL cells. Using Southern blot analyses and long polymerase chain reaction (PCR) we examined HTLV-I provirus in 72 cases of ATL, of various clinical subtypes. Southern blot analyses revealed that ATL cells in 18 cases had only one long terminal repeat (LTR). Long PCR with LTR primers showed bands shorter than for the complete virus (7.7 kb) or no bands in ATL cells with defective virus. Thus, defective virus was evidence in 40 of 72 cases (56%). Two types of defective virus were identified: the first type (type 1) defective virus retained both LTRs and lacked internal sequences, which were mainly the 5’region of provirus, such as gag and pol. Type 1 defective virus was found in 43% of all defective viruses. The second form (type 2) of defective virus had only one LTR, and 5'-LTR was preferentially deleted. This type of defective virus was more frequently detected in cases of acute and lymphoma-type ATL (21/54 cases) than in the chronic type (1/18 cases). The high frequency of this defective virus in the aggressive form of ATL suggests that it may be caused by the genetic instability of HTLV-I provirus, and cells with this defective virus are selected because they escape from immune surveillance systems.

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a southwest oncology group study
By James K. Weick, Kenneth J. Kopecky, Frederick R. Appelbaum, David R. Head, Laura L. Kingsbury, Stanley P. Balcerzak, John N. Bickers, H.E. Hynes, Jeanna L. Welborn, Sheryl R. Simon, and Michael Grever

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/m2/d for 7 days by continuous infusion or HDAC at 2 g/m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = 0.96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = 0.41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC induction (P = 0.049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = 0.0033) and neurologic (P < 0.0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = 0.77 and 0.46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.

A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia
By E. Wattel, A. Guerci, B. Hecquet, T. Economopoulos, A. Copplestone, B. Mahé, M.E. Couteaux, L. Resegotti, V. Voglova, C. Foussard, B. Pegourié, J.L. Michaux, E. Deconinck, A.M. Stoppa, G. Mufti, D. Oscier, P. Fenaux
Groupe Français des Myélodysplasies and European CMML Group

We performed a randomized study of hydroxyurea (HY) versus VP16 in advanced chronic myelomonocytic leukemia (CMML) patients with CMML (according to French-American-British group criteria) and either documented visceral involvement (excluding liver and spleen infiltration) or at least 2 of the following: (1) neutrophils > 16 x 109/l (2) Hemoglobin < 10 g/dL (3) platelets < 100 x 109/L (4) marrow blasts > 5% (5) spleen > 5 cm below costal margin were eligible for this trial. Initial dosage was 1 g/d for HY and 150 mg/week for VP16, orally (doubled in case of visceral involvement). Doses were scheduled to be escalated up to HY 4 g/d and VP16 600 mg/week in the absence of response, and finally adjusted to maintain white blood cells (WBCs) between 5 and 10 x 109/L. Crossing over was scheduled only in case of life threatening visceral involvement or major progression. The major endpoint of the study was survival. The study was closed on first interim analysis that showed a superiority of HY over VP16, after inclusion of 105 pts (HY arm: 53, VP16 arm: 52). Results of the second interim analysis, performed 7 months letter, are presented here. Median age was 71 (range 38 to 91), median WBC count 20.109/L (range 10 to 187). Thirteen pts had visceral involvement (3 serous effusions, 8 cutaneous infiltrations, 1 kidney, 1 bone infiltrations). Initial characteristics were similar in the HY and VP16 groups. Median follow up was 11 months in both groups (range 1 to 43+). Response to treatment was seen in 60% of the pts in the HY group, versus 36%, respectively, in the VP16 group (P = 0.02). Time to response was significantly shorter in he HY group (2.1 v 3.5 months, in the VP16 group, P = 0.003) and response duration was significantly longer in the HY group (median 24 v 9 months, in the VP16 group, P = 0.0004). The response rate of patients with visceral involvement was 3 out of 7 in the VP16 arm versus 5 out of 6 in the HY group. Three of the 10 pts crossed over from HY to VP16 responded as compared to 6 pts of the 11 pts crossed over from VP16 to HY. HY yielded better response on leukocytosis (P = 0.002). The effect on splenomegaly platelets, on hemoglobin level and transfusion requirement was similar in the 2 treatment groups. A significantly higher incidence of alopecia was noted in the VP16 arm (20% v 3%, P = 0.03). Fourteen (27%) and 20 (38%) patients in the HY and the VP16 group respectively, progressed to acute myeloid leukemia (difference NS). Twenty-five (53%) and 44 (83%) patients in the HY and the VP16 group, respectively, had died (P = 0.002). Median actuarial survival was 20 months in the HY arm, versus 9 months in the VP16 arm (P < 10-4). Main factors associated with poor survival were allocation to the VP16 arm, “unfavorable” karyotype (ie, monosomy 7 or complex abnormalities) and anemia. In the HY group, unfavorable karyotype (P = 0.006), and low hemoglobin level (P = 0.004) were significantly associated with low response rates. Prognostic factors for poor survival in the HY group were also unfavorable karyotype (P = 0.001), and low hemoglobin level (P < 10-4). In conclusion, we found that HY gave higher response rates and better survival than VP16 in advanced CMML. However, even with HY responses were only partial and survival was generally poor. This stresses the need for new agents in the treatment of CMML, that will have to be compared with HY in future randomized studies.