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Luiz Eduardo Atalécio

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Hepatocellular carcinoma: from gene to public health
R. Montesano, P. Hainaut, C.P. Wild

Liver diseases associated with chronic hepatitis B virus (HBV) infection, including hepatocellular carcinoma, account for more than 1 million deaths annually worldwide. In addition to HBV infection, other risk factors are involved in the etiology of hepatocellular carcinoma and, among these, dietary exposure to the carcinogenic aflatoxins is of particular importance in certain regions of southeast Asia and sub-Saharan Africa. The relative contributions of these two risk factors and the mechanism of the interaction between them in the pathogenesis of hepatocellular carcinoma are still poorly understood. The recently developed individual biochemical and molecular markers of aflatoxin exposure, i.e., aflatoxin-albumin adducts in blood and a sepecific GC to TA transversion mutation in codon 249 of the p53 gene (249^ser p53 mutation) in hepatocellular carcinomas, permit a better quantitative estimation of aflatoxin exposure in different populations of the world. A comprehensive summary of the data from our laboratory and the literature, based on a large number (> 1000) of individual cases of hepatocellular carcinoma, is presented here and shows the following: 1) A high level and high prevalence of exposure to aflatoxins occur in West Africa, Mozambique, and some regions of China; 2) a high prevalence of the 249^ser p53 mutation is detected in these countries; and 3) hepatocellular carcinomas from countries with low or no exposure to aflatoxins show a very low prevalence of the 249^ser p53 mutation and distinctly different p53 mutation spectra, probably indicating different etiologies. Experimental and epidemiologic studies demonstrate an interaction between HBV infection and aflatoxins in hepatocarcinogenesis. The relevance of the biochemical/molecular markers of aflatoxin exposure, HBV vaccination, and the reduction of aflatoxin exposure, in addition to the interaction between HBV infection and other risk factors in liver carcinogenesis, are discussed with regard to the implementation of measures for primary prevention.

5-HT₃ receptor antagonists: differences and similarities
F. Roila¹, E. Ballatori², M. Tonato1¹ and A. Del Favero³

¹ Medical Oncology Division, Policlinico Hospital, 06122 Perugia;
² Medical Statistics Unit, Department of Internal Medicine, University L’Aquila; and
³Department of Internal Medicine and Oncological Sciences, University, Perugia, Italy

Differences among 5-HT₃ receptor antagonists have been reported in pharmacological studies with regard to selectivity of receptor binding, potency, duration of action and dose-response curves. However, whether these pharmacological differences can affect clinical efficacy and safety remains to be determined. A careful analysis of the literature revealed 22 comparative studies among the 5-HT₃ receptor antagonists available for review. Unfortunately, several of these trials have some important shortcomings especially in the study design, the size of population studied and the type of anti-emetic treatment selected, making their conclusions often difficult to interpret. However, among these studies, seven large, double-blind clinical trials have clearly shown that the antiemetic activity and tolerability of ondansetron, gramisetron, tropisetron and dolasetron is almost identical at least in the prevention of cisplatin-induced emesis. Therefore, from the efficacy and safety point of view, there is no reason to prefer one with respect to the other compound. From the economic perspective, instead, differences may exist and they are strictly related to the dose and schedule of administration chosen for each compound. The information available on the use of 5-HT₃ receptor antagonists in the prevention of emesis induced by moderately emetogenic chemotherapy is at best scant. Contrasting results have been reported and only one well-conducted study has been published in full. Therefore, the possible differences among the various compounds are difficult to evaluate. More studies should be carried out in this group of patients.

The international neuroblastoma risk groups (INRG): a preliminary report
R.P. Castleberry, J. Pritchard, P. Ambros, F. Berthold, G.M. Brodeur, V. Castel, S.L. Cohn, B. De Bernardi, C. Dicks-Mireaux, D. Frappaz, G.M. Haase, M. Haber, D.R. Jones, V.V. Joshi, M. Kaneko, J.T. Kemshead, P. Kogner, R.E.J. Lee, K.K. Matthay, J.M. Michon, R. Monclair, B.R. Roald, R.C. Seeger, P.J. Shaw, H. Shimada and J.J. Shuster
The International Neuroblastoma Working Group sponsored by the William G. Forbeck Research Foundation, Hilton Head Island, South Carolina, U.S.A. and the Neuroblastoma Society of the United Kingdom

Neuroblastoma is the most common solid malignancy of childhood. The enigmatic nature of this tumor has long been recognized [1]; some tumors demonstrate spontaneous resolution following minimal or no therapy while others present at diagnosis with widely spread disease and are virtually always associated with poor survival in spite of modern therapy. In large part, improvements in outcome of children with neuroblastoma have stemmed from a greater ability to distinguish cases of varying risk allowing therapy to be tailored according to risk of recurrent disease. Previously, prognostic stratification was based on stage and age alone but more recently has also incorporated selected biological features. The refinement of clinical/biological prognostication models has been impeded by (1) the different systems for staging and evaluating neuroblastoma used by the principal neuroblastoma research groups worldwide and (2) by the lack of patient numbers required to conduct the multivariate analyses necessary for distinguishing the most predictive groupings of clinical and biological features.

Beginning in 1986, there have been a series of conferences, sponsored by the William Guy Forbeck Research Foundation and the Neuroblastoma Society of the United Kingdom, to address these problems and initiate strategies to overcome them. The first meeting in Hilton Head, South Carolina, U.S.A., convened clinical and laboratory neuroblastoma researchers from 13 countries and focused upon standardising staging and clinical assessment. The result was the development of the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Response Criteria (INRC) [2]. The INSS/INRC combined the most frequently used systems and definitions in the countries represented [3-6] and, for the first time, provided an opportunity for the international neuroblastoma research community to generate data from clinical and laboratory studies which could be compared. When the INSS/INRC were applied over the ensuing 4 years, some problems with interpretation were identified which impeded universal implementation [7]. This prompted the second INSS/INRC workshop in October, 1991. While major revisions in the INSS/INRC were not necessary, the areas of contention were clarified and it was agreed that the changes made would streamline integration of the INSS/INRC into the neuroblastoma research community [8]. The revised INSS criteria, detailed in Table 1, have gained universal acceptance.

The second INSS/INRC working group also discussed the emerging importance of biological variables for predicting outcome, independent of stage and age. It was recommended that a prospective effort be launched to construct and evaluate International Neuroblastoma Risk Groups (INRG), representing a composite of age, INSS stage and the most predictive biological variables [8]. Such was the proposed objective for the third INSS/INRG conference. Before embarking on this study, three specific aims had to be realized: (1) to determine which biological variables, based upon universal availability and prognostic power, should be incorporated into the INRG; (2) to develop the infrastructure necessary to test the INRG and (3) to assess the feasibility of combining data sets from the various neuroblastoma research groups worldwide. To accomplish these aims, three international subcommittees (Pathology, Immunobiology, Statistics) were established (Figure 1). We report here a summary of the deliberations of these subcommittees and of the third meeting of the INSS/INRG working group (Berkeley, U.K., September, 1995).

Gene therapy - promises, problems and prospects
Inder M. Verma and Nikunj Somia

In principle, gene therapy is simple: putting corrective genetic material into cells alleviates the symptoms of disease. In practice, considerable obstacles have emerged. But, thanks to better delivery systems, there is hope that the technique will succeed.

In 1990, the first clinical trials for gene-therapy approaches to combat disease were carried out. Conceptually, the technique involves identifying appropriate DNA sequences and cell types, then developing suitable ways in which to get enough of the DNA into these cells. With efficient delivery, the therapeutic prospects range from tackling genetic diseases and slowing the progression of tumors, to fighting viral infections and stopping neurodegenerative diseases. But the problems - such as the lack of efficient delivery systems, lack of sustained expression, and host immune reactions - remain formidable challenges.

Although more than 200 clinical trials are currently underway worldwide, with hundreds of patients enrolled, there is still no single outcome that we can point to as a success story. To explore why this is the case, we will use our own experience and other examples to look at the many technical, logistical and, in some cases, conceptual hurdles that need to be overcome before gene therapy becomes routine practice in medicine.

At present, gene therapy is being contemplated only on somatic (essentially, non-reproductive) cells. Although many somatic tissues can receive therapeutic DNA, the choice of cell usually depends on the nature of the disease. Sometimes a clear definition of the target cell is needed. For example, the gene that is defective in cystic fibrosis has been identified, and clinical trials to deliver DNA as an aerosol into the lung have already begun1. Although cystic fibrosis is manifest in this organ, it is still not clear that delivery of a correcting gene by this method will reach the right type of cell. On the other hand, to correct blood-clotting disorders such as haemophilia, all that is needed is a therapeutic level of clotting protein in the plasma2. This protein may be supplied by muscle or liver cells, fibroblasts, or even blood cells3-5. The choice of tissue in which to express the therapeutic protein will also ultimately depend on considerations such as the efficiency of gene delivery, protein modifications, immunological status, accessibility and economics.

Cancer genetics - Survey of primary care physicians' attitudes and practices
Lois C. Friedman, PhD, Sharon E. Plon, MD, PhD, H. Paul Cooper, MA and Armin D. Weinberg, PhD

Abstract-Background. Genetic testing for susceptibility to cancer often involves complex medical, ethical, legal, and psychological issues that present a challenge for physicians in clinical practice. Methods. This study is based on survey data from 101 primary care physicians throughout Texas, measuring their interest in and attitudes about cancer genetics. Results. The majority of physicians surveyed reported that they would consider genetic screening for at least one of seven genetic disorders that predispose to cancer, and almost 20% had made one or more referrals for genetic evaluation and DNA testing. Overal, they wanted to see a variety of continuing education programs and educational materials on DNA testing for cancer susceptibility developed. Although most of the physicians accurately perceived a number of major obstacles to referring patients for genetic testing, barriers such as difficulty in interpreting test results, potential for false-positive and false-negative results, and concern about patients’ reactions to test results were reported less frequently. Conclusions. The results support other evidence for a need to provide continuing education to physicians about genetic testing for susceptibility to cancer.

A retrospective cost-effectiveness analysis of interferon as adjuvant therapy in high-risk resected cutaneous melanoma
A. Messori, P. Becagli, S. Trippoli and E. Tendi
Drug Information Centre, Pharmaceutical Service, Servizio Farmaceutico, Policlinico Careggi Hospital, Azienda Ospedaliera Careggi, Viale Morgagni 85, 50134 Florence, Italy

To assess the cost per life year gained of alpha interferon (IFN) as adjuvant therapy for patients with high-risk resected melanoma, we conducted a retrospective, incremental cost-effectiveness analysis on clinical data from a previously published ECOG trial [9]. The Gompertz model was used to estimate the total lifetime values of patient-years of subjects receiving IFN in comparison with subjects given no adjuvant treatment. The ECOG trial involved 143 patients treated with high-dose IFN and 137 given no adjuvant treatment. Estimated drug expenditures were based on the assumption of a cost of $ 109.25 per 10 UM of IFN. Our analysis of the ECOG results showed that the adjuvant treatment of 100 subjects with high-dose IFN improved survival expectancy by 133.6 discounted life years or 308 undiscounted life years. The use of IFN (compared with no adjuvant treatment) implied an incremental cost of $ 16467 per discounted life year saved (95% CI of $ 4752-50.000) or $ 7143 per undiscounted life year saved (95% CI of $ 3226-33846). Sensitivity testing, in which variations were introduced in the main factors influencing cost and effectiveness, showed that this value always remained below $ 50.000. Our pharmacoeconomic analysis indicates that adjuvant treatment with high-dose IFN in patients with high-risk resected melanoma implies a favourable cost-effectiveness ratio. Because two other studies showed no significant survival benefit in patients receiving adjuvant IFN at lower values of total dose per patient, the controversy remains and confirmation data are needed for the ECOG trial’s results. If these clinical results are confirmed, our analysis shows that the dosage of IFN given in this trial has a favourable pharmacoeconomic profile.

Should high-dose chemotherapy be used in the treatment of soft tissue sarcoma?
P. Reichardt, J. Verweij and D. Crowther
Pro:
P. Reichardt
Department of Haematology, Oncology and Tumorimmunology, Robert-Rössle-Hospital, Virchow Medical Center, Humboldt University, Lindenberger Weg 80, D-13125 Berlin, Germany

'Grade 3 nausea, vomiting, and myelosuppression or progressive, metastatic sarcoma?' This was the provocative title of an editorial by R.S. Benjamin in the Journal of Clinical Oncology in 1987 [1]. The author had analyzed several clinical trials and stated that dose intensity resulting in more or less severe myelosuppression was a prognostic factor. He concluded that, for best results, the most active drugs should be given at doses high enough to produce myelosuppression.

In contrast to chemosensitive diseases such as lymphoma or breast cancer the number of active drugs against soft tissue sarcoma is very limited. Besides doxorubicin and epirubicin, only ifosfamide shows significant and consistent activity. The role of DTIC is questionable at least in non-leiomyosarcoma and the possible fourth drug, docetaxel, remains to be further investigated [2]. So far, new active drugs are not in sight. The only possibility of improving results is to optimise current treatment strategies, using the best drugs in the best possible way.

Doxorubicin [3, 4] and epirubicin [5-7] have been shown to have steep dose-response curves in different tumor types, including soft tissue sarcoma. A dose-response relationship has also been established for ifosfamide [8], high-dose ifosfamide being he only active drug in pretreated patients even after standard-dose ifosfamide [9-12]. Due to overlapping myelosuppression, most studies on combination chemotherapy used doxorubicin at doses below those in single drug therapy, thus compromising its activity.

Results of randomised studies comparing single-agent to combination chemotherapy are conflicting.

Soft tissue sarcomas
R.B. Womer
Division of Oncology, The Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.

Introduction
The soft tissue sarcomas of childhood are dominated by one diagnosis, rhabdomyosarcoma. Thus, any discussion of these tumors is similarly dominated. In rhabdomyosarcoma, there has been considerable biological and clinical progress, although a few very important biological, pathological and therapeutic questions are still unanswered. The other (‘non-rhabdo’ or ‘miscellaneous’) soft tissue sarcomas, while not subject to great therapeutic ferment, are beginning to fall under systematic clinical scrutiny and several have had their tumor-specific translocations cloned.

Ewing's sarcoma of the pelvis: changes over 25 years in treatment and results
J.M.V. Burgers^1*, F. Oldenburger², J. de Kraker², B.N.F.M. van Bunningen¹, J.W. van der Eijken², J.F.M. Delemarre^1,2, C.R. Staalman² and P.A. Vo&uacirc;te²

¹The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Department of Radiotherapy and Pathology, Plesmanlaan 121, 1066 CX Amsterdam; and
²Emma Kinder Ziekenhuis/A.M.C., Department of Paediatric Oncology, Radiotherapy and Pathology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1005 AZ Amsterdam, The Netherlands

The pelvic localizations of Ewing's sarcoma have the worst prognosis due to large size at diagnosis, frequent distant metastases, radiosensitive organs next to the tumor and difficult surgery. The purpose of the present study was to analyze treatment results over a period of 25 years and to investigate the impact of newer chemotherapy schedules, improved radiotherapy techniques and newer surgical methods on the prognosis. 35 children and young adults were identified from 1967 to 1994 for whom diagnosis, presentation, performed treatment and outcome were available. Tumour size, as measured from CT scans, response to chemotherapy and radiotherapy target volume, could be reviewed in the later years. Actuarial 5-year survival for the whole group was 31% and for the 24 non-metastatic patients 40%, with a disease-free interval of 19%. Tumour size could be measured in 27 patients and ranged from 36 to 1540 cm3. There were 12 local recurrences, 1 in the 4 patients treated with surgery. After 1983, 9 out of 17 irradiated patients developed local failure. 3 patients had adequate fields and one a close field which did not cover completely the prechemotherapy extent and 3 of these recurred. All 4 patients with stable disease after neoadjuvant CT failed locally, not withstanding high-dose radiotherapy. The mean length of neoadjuvant CT tended to be shorter in patients without local relapse. There was no significant difference in survival before and after 1983.

Growth Inhibition of Human Ovarian Cancers by Cytotoxic Analogues of Luteinizing Hormone-Releasing Hormone
Masahiro Miyazaki, Attila Nagy, Andrew V. Schally, Najib Lamharzi, Gabor Halmos, Karoly Szepeshazi, Kate Groot, Patricia Armatis

Background: Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in nearly 80% of human ovarian cancers. The chemotherapeutic agent doxorubicin can be linked to [D-lysine⁶] LH-RH to form a cytotoxic analogue (AN-152) that may have greater specificity for tumor cells. This study was conduced to investigate the effects of AN-152 on the growth of LH-RH receptor-positive OV-1063 human epithelial ovarian cancers. Methods: Nude mice bearing human ovarian tumors, OV-1063 or UCI-107 (LH-RH receptor negative), were injected intraperitoneally with saline (control) or with equimolar doses of AN-152 or doxorubicin; experiments involving mice with OV-1063 tumors also included groups that were administered [D-lysine⁶] LH-RH either alone or in combination with doxorubicin. Tumor volume, weight, doubling time, and burden (i.e., tumor weight/body weight) as well as tumor apoptotic and mitotic indices were determined. The levels of receptors for LH-RH and epidermal growth factor (EGF) and their messenger RNAs were measured by use of radioreceptor and reverse transcription-polymerase chain reaction assays, respectively. Results: The growth of OV-1063 ovarian tumors in nude mice, as based on reduction in tumor volume, was inhibited significantly (all P < 0.05, two-sided) 4 weeks after treatment with AN-152, even at the lowest dose tested (413 nmol/20 g weight); the toxic effects of an equivalent dose of doxorubicin caused substantial mortality. High-affinity receptors for LH-RH and EGF were found on cell membranes of OV-1063 cancers; however, after in vivo treatment with AN-152, LH-RH receptor-binding sites were not detectable and EGF receptors were reduced in number. The growth of UCI-107 ovarian cancers was not inhibited by AN-152. Conclusions: In nude mice bearing LH-RH receptor positive OV-1063 epithelial ovarian cancers, systemic administration of AN-152 is less toxic and inhibits tumor growth better than equimolar doses of doxorubicin.

Phase II trials of docetaxel (Taxotere®) in advanced ovarian cancer - an updated overview
S.B. Kaye¹, M. Piccart², M. Aapro³, P. Francis⁴ and J. Kavanagh⁵

¹Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, U.K.;
²Institut Jules Border, Department of Chemotherapy, Rue Héger-Bordet 1, 1000 Brussels, Belgium;
³Genolier Cancer Center, Clinique de Genolier S.A. CH 1272 Genolier, Switzerland;
⁴Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 100021, U.S.A.; and
⁵MD Anderson Cancer Center, University of Texas, Division of Medicine, Box 39, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, U.S.A.

Docetaxel (Taxotere®) has been studied at a dose of 100 mg/m² i.v. as a one hour infusion every 3 weeks, in four phase II trials in patients with extensively pretreated ovarian cancer. A total of 340 patients were treated, including 256 patients in two separate EORTC (European Organization for Research and Treatment of Cancer) trials and 84 patients in two trials in the U.S.A. All patients had received prior cisplatin or carboplatin therapy and the treatment-free interval was less than 4 months in 155 patients. The overall response rate using conventional UICC criteria was 30% among 315 evaluable cases (95% confidence interval: 24-36%). Among 155 patients whose disease was most refractory (i.e. treatment-free interval was less than 4 months), the overall response rate was 28% (95% confidence interval: 19-36%). Response duration ranged from 4 to 17 months. Grade IV neutropenia was a common finding and fluid retention was observed. The incidence of febrile neutropenia ranged from 8 to 44% of patients with two deaths (i.e. 0.6% of the total treated) related to neutropenic sepsis. Docetaxel and paclitaxel (Taxol®) have comparable activities in ovarian cancer. Ongoing studies with docetaxel include its use in patients as part of first-line therapy, as well as in patients refractory to paclitaxel. To prevent the development of fluid retention, these now involve the routine use of steroid prophylaxis. It is expected that docetaxel will prove to be an important addition to the drugs available for the treatment of ovarian cancer.

Whole-abdomen radiation therapy as salvage treatment for epithelial ovarian carcinoma
Thomas V. Sedlacek, MD, Pericles Spyropoulus, MD, Ralph Cifaldi, DO, John Glassburn, MD and Scot Fisher, DO, Philadelphia, Pennsylvania

PURPOSE
This study aimed to evaluate the efficacy and safety of whole-abdomen radiation therapy as salvage treatment in patients with ovarian cancer.

PATIENTS AND METHODS
Twetny-seven patients who failed aggressive cytoreductive surgery followed by multiple-drug platinum-based chemotherapy were found to have recurrent epithelial carcinoma of the ovary and were treated with whole-abdomen radiation as salvage therapy. Dosage fractions were planned at 100 to 150 cGy daily to 3000 to 3500 cGy, followed by a pelvic boost at 150 to 180 cGy daily. All patients completed the planned treatment. The average treatment program required 53,5 (range, 42-71 days).

RESULTS
Survival rates at years 1 through 5 were 66%, 48%, 26%, 15%, and 15%, respectively. Residual disease at initiation of radiation correlated strongly with length of survival. The patients with microscopic disease survived and average of 63 months (range, 30-111 months). Patients with disease larger than 2 cm survived an average of 9 months (range, 5-17 months). Toxicity was seen in all patients. Eight patients experienced grade 3 or 4 toxicity, primarily white blood cell count and gastrointestinal toxicity. There were no deaths related to toxicity.

DISCUSSION
This experience strongly suggests that whole-abdomen radiation is a viable salvage option, especially for patients with microscopic retroperitoneal disease or small-volume macroscopic disease.

Extracapsular invasion of lymph node metastasis is an indicator of distant metastasis and poor prognosis in patients with thyroid papillary carcinoma
Hiroto Yamashita, M.D., Ph.D.¹, Shiro Noguchi, M.D., Ph.D.², Nobuo Murakami, M.D.², Hitoshi Kawamoto, Ph.D.² and Shin Watanabe, M.D.²

Background: In patients with thyroid papillary carcinoma, age and the presence or absence of distant metastasis are regarded as the main prognostic factors. However, the histologic characteristics of thyroid papillary carcinoma that develops distant metastasis have not yet been clarified. Methods. The histologic findings and prognosis of 50 patients with thyroid papillary carcinoma who later developed distant metastasis (metastatic group) were compared with those of 50 patients without local recurrence or distant metastasis (control group). The age, tumor size, and gender ratio of the control group were matched with those of the metastatic group. Univariate analyses (chi-square test and/or Fisher's exact test) and multivariate analyses (logistic regression) were performed. Results. Univariate analyses showed that the incidence of nonpure papillary carcinoma, absence of bone at the periphery of the tumour, invasion of the perithyroidal muscle, large lymph node deposits, and extranodal invasion were significantly higher in the metastatic group. Multivariate analyses revealed that only extranodal invasion was statistically significant (P = 0.0045) and that the odds ratio of extranodal invasion in distant metastasis was 9. Moreover, the risk of death from thyroid carcinoma was higher among the patients with extranodal invasion than those without (P < 0.01). Conclusions. The presence of extranodal invasion in patients with thyroid papillary carcinoma is an indicator of distant metastasis and poorer prognosis.

A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting highlights and Bethesda guidelines
Miguel A. Rodriguez-Bigas, C. Richard Boland, Stanley R. Hamilton, Donald E. Henson, Jeremy R. Jass, P. Meera Khan, Henry Lynch, Mauel Perucho, Thomas Smyrk, Leslie Sobin, Sudhir Srivastava

Hereditary nonpolyposis colorectal cancer (HNPCC) is a distinct autosomal dominant syndrome accounting for approximately 5%-6% of the total colorectal cancer burden with clinical and pathologic features caused by defective mismatch repair genes (1). Germline mutations in hMSH2, hMLH1, hPMS1, hPMS2, and MSH6/GTBP have been identified in affected individuals (2, 3). HNPCC is characterized by early-onset colorectal cancer (median age at diagnosis 45 years); right-sided predominance; excess synchronous and metachronous colorectal neoplasms; and an increased incidence of extracolonic neoplasms, including endometrial, small-bowel, gastric, renal pelvis and ureter, and ovarian tumors and skin lesions, such as sebaceous adenomas, carcinomas, and keratoacanthomas (4-10).

In 1991, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (11) established minimal clinical criteria for recruiting HNPCC patients for collaborative studies. These criteria, also known as the Amsterdam Criteria, include the following: 1) at least three relatives with histologically verified colorectal cancer, one of them a first-degree relative of the other two (familial adenomatous polyposis excluded); 2) at least two successive generations affected; and 3) in one of the individuals, diagnosis of colorectal cancer before the age of 50. These criteria were pivotal in identifying kindreds that eventually led to the association of the HNPCC syndrome with germline mismatch repair gene mutations (MMR). However, the criteria do not account for extracolonic cancers or for small kindreds.

On November 11 and 12, 1996, the Early Detection Branch of the National Cancer Institute convened an international workshop in Bethesda, MD, entitled “The Intersection of Pathology and Genetics in the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome.” The purpose of the workshop was to clarify the role of genetics in the pathology of HNPCC. Discussions centered on genomic instability, multistep carcinogenesis and the role of mismatch repair genes in HNPCC, histopathology of HNPCCs and possible relationships to molecular genetic changes, markers of cell proliferation and their relationship to HNPCC as well as their potential use in early diagnosis and prognosis, and, lastly, clinicopathologic criteria that could lead to the identification of additional HNPCC patients. The keynote speaker was Dr. Alfred Knudson (Fox Chase Cancer Center, Philadelphia), who discussed the tumor spectrum of the HNPCC syndrome. Issues that arose during the workshop are discussed below.

Adjuvant therapy for colon cancer
John S. Macdonald, MD

Colorectal cancer represents a significant health problem in the United States. It is estimated that there will be approximately 131,000 cases of cancer of the colon and rectum in 1997¹. Of these malignancies, approximately 37,000 will be confined to the rectum and the remainder will be in the colon. Although there is interest currently in the evaluation of molecular markers (ploidy^2-4and tumor suppressor gene mutation or deletion^5-7) as prognostic markers, the most important prognostic information available to clinicians managing patients with colorectal cancer is still surgical pathologic staging of the resected primary tumor⁸. Patients with locally advanced (Dukes stages B2, B3, and C; TNM stages II and III) large bowel cancer have a significantly increased risk of relapse after surgical resection alone (Table 1). In stage III patients, the risk of death from cancer is 30% to 60% during the 5 years after surgical resection.

Because of the high risk of relapse after surgery alone, therapies that may be added to surgery to prevent clinical metastatic disease have attracted great interest. Many adjuvant chemotherapy trials have been performed in colon cancer over the last 30 years^8-10. This article will briefly review the status of adjuvant therapy in colon cancer.

Malignant effusions
A.-G. Maiche
Department of Oncology, Mafraq Hospital, P.O. Box 2951, Abu-Dhabi, UAE.

INTRODUCTION
Effusions are Common in advanced cancer. Caused by direct or indirect action of cancer cells or tumors, fluids can accumulate in the interpleural space (pleura effusion), intrapericardially (pericarditis and cardiac tamponade) or intraperitoneally (ascites). Mechanisms of formation of effusions are related to situations increasing fluid production and to factors impeding fluid outflow (Table I). This results in increasing accumulation of fluids and leads to severe symptoms and deterioration of the patient’s general condition. Depending on the mechanism of fluid formation, malignant effusions are classified as transudate, exudate and chyle (Table II).

Prognosis in cancer has often been related to the presence or absence of effusion (1) (2). The presence of intraperitoneal effusion is considered to be a sign of a very poor prognosis and is associated with the terminal stage of cancer.

Treatment of malignant effusions has, except in malignant lymphomas where complete cure could be achieved with systemic chemotherapy, almost always a palliative care character. Different methods of treatment are available, but continuous drainage of the effusion and intracavitary use of sclerosing agents or cytostatics have been successfully employed during the last decades (3). Complete control of effusions has been increasingly achieved with the development of more efficient agents.

Many agents have shown great efficacy in the treatment of malignant effusions (Table III). Criteria for considering an agent for intracavitary treatment are efficacy, low toxicity, especially if instilled intraperitoneally, rapid metabolism to non-toxic metabolites, low absorption into the system, and slow exit from the cavity. A slower exit from the cavity would allow a more extensive action of the agent.

Cigarette smoking and changes in the histopathology of lung cancer
Michael J. Thun, Cathy A. Lally, John T. Flannery, Eugenia E. Calle, W. Dana Flanders and Clark W. Health, Jr.

Background: Adenocarcinoma of the lung, once considered minimally related to cigarette smoking, has become the most common type of lung cancer in the United States. The increased incidence of this cancer might be explained by advances in diagnostic technology (i.e., increased ability to perform biopsies on tumors in smaller, more distal airways), changes in cigarette design (e.g., the adoption of filtertips), or changes in smoking practices. We examined data from the Connecticut Tumor Registry and two American Cancer Society studies to explore these possibilities. Methods: Connecticut Tumor Registry data from 1959 through 1991 were analyzed to determine whether the increase in lung adenocarcinoma observed during that period could be best described by birth cohort effects (i.e., generational changes in cigarette smoking) or calendar period effects (i.e., diagnostic advances). Associations between cigarette smoking and death from specific types of lung cancer during the first 2 years of follow-up in Cancer Prevention Study I (CPS-I, initiated in 1959) and Cancer Prevention Study II (CPS-II, initiated in 1982) were also examined. Results: Adenocarcinoma incidence in Connecticut increased nearly 17-fold in women and nearly 10-fold in men from 1959 through 1991. The increases followed a clear birth cohort pattern, paralleling gender and generational changes in smoking more than diagnostic advances. Cigarette smoking became more strongly associated with death from lung adenocarcinoma in CPS-II compared with CPS-I, with relative risks of 19.0 (95% confidence interval [CI] = 8.3-4.7] for mean and 8.1 (95% CI = 4.5-14.6) for women in CPS-II and 4.6 (95% CI = 1.7-12.6) for mean and 1.5 (0.3-7.7) for women in CPS-I. Conclusions: The increase in lung adenocarcinoma since the 1950s is more consistent with changes in smoking behavior and cigarette design than with diagnostic advances.

Tumor regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment
K. Junker, M. Thomas, K. Schulmann, F. Klinke, U. Bosse and K.-M. Müller

AbstractIn the scope of a prospective multi-centre stud after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analyzed in order to establish reproducible pathological anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a three-step regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumor regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB our III tumour regression (“responders”) the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression (“non-responders”) with a median survival period of 13.7 months (log-rank test, P = 0.020). The resection specimens analyzed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumor regression could be shown to be a significant prognostic factor in non-small-cell lung cancer.

Response to chemotherapy has predictive value for further survival of patients with advanced non-small cell lung cancer: 10 years experience of the European Lung Cancer Working Party
M. Paesmans, J.P. Sculier, P. Libert, G. Bureau, G. Dabouis, J. Thiriaux, J. Michel, O. Van Cutsem, R. Sergysels, P. Mommen and J. Klastersky for the European Lung Cancer Working Party
Unité de Biostatistique, Service de Médecine et Laboratoire d'Investigation Clinique et d’Oncologie Expérimentale H.J. Tagnon, Institut Jules Bordet, 1 rue Héger-Bordet, B-1000 Bruxelles, Belgium

The aim of this study was the assessment of the predictive value for survival of an antitumoral response to three courses of chemotherapy in association with various pretreatment characteristics in patients with non-resectable non-small cell lung cancer treated by cisplatin- (or carboplatin)-based combination regimens. Patients considered for this study were eligible patients with advanced non-small cell lung cancer registered in one of the seven trials conducted by the European Lung Cancer Working Party from December 1980 to August 1991. All these trials tested chemotherapy regimens with platinum derivative (cisplatin and/or carboplatin). In this population of 1052 eligible patients, 752 were assessed in this analysis. Data were prospectively collected on 23 pretherapeutic variable and objective response after three chemotherapy cycles. The predictive value of response to chemotherapy on survival (measured from the time of response assessment i.e. 12 weeks after registration in the trial) was studied by univariate analysis as well as by multivariate methods (adjustment of the impact of several covariates simultaneously on the dependent variable) with adjustment for the pretreatment prognostic variables. After three cycles of chemotherapy, the global estimated median survival time was 24 weeks with a 95% confidence interval of 22-25 weeks. By univariate analysis, we identified an objective response to chemotherapy as a highly significant discriminant marker (P < 0.0001) for further survival with estimated median survival times of 41 weeks (95% CI: 38-46) and 19 weeks (95% CI: 17-20), respectively, for the responding and non-responding patients. In a Cox regression model fitted to the data using a forward stepwise procedure, this variable was the first selected explanatory variable. Its effect was adjusted by the introduction in the model of initial disease extent, Karnofsky performance status, serum calcium level and white blood cell count. These results were consistent with which led to a classification of the patients into three homogeneous subgroups. Our results, using a classical Cox regression model consistent with those highlighted by application of a RECPAM analysis, found an objective response to chemotherapy to be a predominant predictive factor for further survival, although it did not allow any conclusion about a causal relationship. The RECPAM results led to a classification of the patients into three subgroups which needs to be validated in other series.

Preserving scientific debate and patient choice
Lessons from the consensus panel on mammography screening
Steven Woolf MD, MPH and Robert Lawrence MD

The National Institutes of Health (NIH) convened a consensus conference in January 1997 to examine new evidence on the effectiveness of mammographic screening for breast cancer in women ages 40 to 49 years. After reviewing the data and hearing testimony from experts and advocates, the panel concluded that the evidence did not support a universal recommendation for or against routine mammography in this age group¹. The panel advised each woman to decide with her physician, based on her personal values and risk factors, whether to have the test. Critics denounced this recommendation, accusing the panel of distorting the evidence and misleading the public². News accounts emphasized the acrimony among health professionals and medical groups³. The US Senate passed a resolution repudiating the panel, demanded revised guidelines, and convened investigative hearings^{4, 5}. Finally, in March the American Cancer Society and National Cancer Institute (NCI) recommended that all women should begin routine mammographic screening by the age of 40 years⁶.

This incident is worthy of attention, not so much to resolve the debate about screening mammography in younger women, but to examine the process by which the debate was conducted. In the rush to repudiate the panel, we believe that critics ran roughshod over the precepts of scientific debate and patient autonomy. The panel, critics said, reached the "wrong" conclusion about the data, erred in not making a recommendation, and should not have invited women to decide for themselves. We worry that such arguments carry ominous implications for the freedom of scientific inquiry and patient self-advocacy, concerns that extend beyond breast cancer. They warrant attention regardless of whether we agree or disagree with the conclusions of the NIH panel.

First, the acrimony itself deserves mention. Participants on either side were quick to question each other's motives. Screening advocates accused panelists of deceiving and injuring American women². Radiologists were accused of bowing to self-interest. Lost in the recriminations was the notion that both sides might have sought what was best for women and simply reached different conclusions from the available data. Animus deserves no place in scientific debate. Objective discourse is at risk if colleagues cannot dispute evidence without being accused of malevolence.

Moreover, the critics' arguments challenge the very principles of scientific inquiry, circumspection, and ethics. Consider the key elements of the panel’s conclusions: (1) the strength of the evidence for mammography is uncertain, (2) universal guidelines are not justified by the data, and ........

Management of cutaneous melanoma M0: state of the art and trends
C.R. Rossi, M. Foletto, A. Vecchiato, S. Alessio, N. Menin and M. Lise
Dipartimento di Scienze Oncologiche e Chirurgiche, Clinica Chirurgica II, Università di Padova, Via Giustiniani 2, 35128 Padova, Italy

This article reviews the epidemiology, diagnosis and treatment of cutaneous melanoma, including the most recent developments. The combination of positive family history, fair complexion, number of nevi, exposure to sun and/or chromosomal alterations seem to be implicated in the pathogenesis of cutaneous melanoma. Melanomas can be classified according to their growth patterns, and tumour microstaging is of straightforward predictive value for survival and risk of metastasis, although new factors are also being investigated. As yet, surgical excision is the only effective treatment available for primary tumours, resection margins varying according to tumour thickness. Elective node dissection is, however, no longer advocated for melanomas thinner than 1.5 mm, and there is disagreement as to its role for thicker lesions. In contrast, selective node dissection at the time of definitive surgery is becoming more widely accepted, with regional node dissection being restricted to positive cases. Therapeutic dissection is required for lymph node involvement, the most common pattern of recurrence from melanoma, which affects nearly 30% of all patients. Complete remission rates from isolated limb perfusion, which has been employed in patients with multiple recurrences or in-transit metastases, range from 40 to 90%, depending on drugs and techniques used in different series; the best responses so far have been obtained with tumour necrosis factor in combination with melphalan. Patients with thick lesions (> 4 mm) or lymph node metastases have a high risk of micrometastases that would warrant adjuvant therapy. The only agent found to affect survival is interferon alpha-2.

Background: Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer. Methods: Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations. Results: Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P < 0.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically. Conclusions: The total cancer prevalence ratio 10.5/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

Pattern of dissemination and survival following isolated locoregional recurrence of breast cancer
A prospective study with more than 10 years of follow up
Claus Kamby^1,2 and Lisa Sengeløv²

¹ Finsen Centre, Rigshospitalet and ² Department of Oncology, Copenhagen University Hospital in Herlev, Denmark

Purposes: The study evaluates prognostic factors for dissemination and survival in patients with local or regional recurrence of breast cancer. Furthermore, the aim was to define subgroups of patients at different risk of developing metastases in specific anatomical sites. Patients and methods: The study included 140 patients with isolated local or regional node recurrence, who entered a prospective study for staging of patients with first recurrence of breast cancer in the period 1983-85. The primary treatment was a simple mastectomy: node positive patients received adjuvant radiotherapy and chemotherapy or tamoxifen. If possible, the locoregional recurrence was treated with surgery and/or radiotherapy, otherwise by systemic therapy. Results: Median follow up was 10.4 years; 78 patients developed distant metastases (soft tissue, 32%; bone, 45%; viscera 40%). Median time to dissemination was 4.4 years, and the ten year dissemination rate was 72%. Median time to dissemination was 3.7 years for patients with recurrence in the regional nodes compared to 6.5 years for patients with chest wall recurrence only, p = 0.05. No specific time sequence (temporal pattern) was observed in the anatomical distribution of metastases, and the anatomical site of recurrence could not be predicted by any of the prognostic factors. At follow up, 93 patients had died. The median survival was 5.6 years and 30% were alive after 10 years. Forty-three of the 99 patients who received local therapy only did not develop metastases. Fifteen of these patients died without evidence of metastatic disease while 28 patients were still alive without distant recurrence after a median follow up time of 9.3 years (range, 6.5-11.9 years). Level of LDH and the number of positive regional nodes (NPOS) at primary diagnosis were significant independent prognostic factors for survival after recurrence. Conclusions: Approximately one third of the patients receiving local treatment only, were alive and without distant metastases up to ten years after locoregional recurrence, indicating that there is a subset of patients which may be long term survivors after local treatment only (surgery or radiotherapy). The duration of survival can be estimated by LDH and NPOS, but the model needs validation in a separate data set before clinical use.

Review of recent trials of chemotherpy for advanced breast cancer: studies excluding taxanes
M. Clemons, M. Leahy, J. Valle, G. Jayson, M. Ranson, S. Hayes and A. Howell
CRC Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, U.K.

INTRODUCTION
A number of new agents and combinations of drug have been introduced for breast cancer over the past 2 years. The purpose of this review is to summarise all trials reported between January 1995 and December 1996.

The process of introducing new agents has become more complex recently. Not only can they be used alone or in combination at the standard dose, but the effect of increasing the dose and reducing the dose interval using haemopoeitic growth factors (HGFs), can also be assessed, as can increasing the dose even further by using peripheral blood progenitor cell (PBPC) support. The complexity of possible potential studies is outlined in Figure 1. Yet another complication of the evaluation of drugs in breast cancer is that treatment may be initiated at different stages of disease, e.g. first- or second-line chemotherapy for advanced disease or for locally advanced disease. In this review we have therefore categorized the studies as follows:

Advanced breast cancer
(a) New combinations of established drugs
(b) Dose intensification using HGFs
(c) Dose intensification using PBPC
Locally advanced breast cancer
Neoadjuvant therapy
New agents

We assessed all reports of breast cancer trials on Medline, BIDS (Bath Information and Data Services) and Abstracts from the major international meetings on cancer. Abstracts were discarded when basic data required for interpretation of the trial were not obvious. Many trials are reported on more than one occasion, and only the most recent or the published paper has been used.

Review of recent trials of chemotherapy for advanced breast cancer: the taxanes
M. Clemons, M. Leahy, J. Valle, G. Jayson, M. Ranson and A. Howell
CRC Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, U.K.

INTRODUCTION
The Taxanes are a relatively new class of chemotherapeutic agents which act specifically on the microtubules of the cell spindle, resulting in disruption of mitosis, and therefore cell proliferation. There are currently two taxanes which have been clinically tested, paclitaxel (Taxol) and docetaxel (Taxotere), and both have shown antitumour activity against breast cancer in clinical trials. These are summarized in this review.

Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer
Bernard Fisher, James Dignam, Norman Wolmark, Arthur DeCillis, Birol Emir, D. Lawrence Wickerham, John Bryant, Nikolay V. Dimitrov, Neil Abramson, James N. Atkins, Henry Shibata, Luc Deschenes and Richard G. Margolese

Background: The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy p lus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. Methods: Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. Results: Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = 0.01]; 89% for CMFT versus 85% for tamoxifen [P = 0.001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = 0.008]; 91% for CMFT versus 87% for tamoxifen [P = 0.006] and survival (97% for MFT versus 94% for tamoxifen [P = 0.05]; 96% for CMFT versus 94% for tamoxifen [P = 0.03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemoteraphy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. Conclusions: Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy.

Biology of cachexia
Michael J. Tisdale

About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle mass. Such patients have a decreased survival time, compared with the survival time among patients without weight loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and nutritional supplementation alone is unable to reverse the wasting process. Despite a falling caloric intake, patients with cachexia frequently show an elevated resting energy expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosis factor-a, interleukins 1 and 6, interferon g, and leukemia-inhibitory factor, have been proposed as mediators of the cachectic process. However, the results of a number of clinical and laboratory studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer cachexia. In addition, cachexia has been observed in some xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably include catabolic factors, which act directly on skeletal muscle and adipose tissue and the presence of which has been associated with the clinical development of cachexia. A polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such catabolic factors and has been shown to stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment of cachexia.

Treatment with cisplatin and fluorouracil alternating with radiation favourably affects prognosis of inoperable squamous cell carcinoma of the head and neck: results of a multivariate analysis on 273 patients
M. Benaso¹, L. Bonelli², G. Numico¹, R. Corvò³, G. Sanguineti³, R. Rosso¹, V. Vitale³ and M. Merlano¹

¹Department of Medical Oncology I, ²Department of Biostatistics, ³Department of Radiation Oncology, National Institute for Cancer Research. Genova, Italy

Purpose: The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III-IV, inoperable, squamous cell carcinoma of the head and neck (SCC-HN). Patients and methods: Between August 1983 and December 1990, 273 patients with stage III-IV, previously untreated, unresectable SCC of the oral cavity, pharynx and larynx, were included into two consecutive randomized multi-institutional trials (HN-7 and HN-8 protocols) coordinated by the National Institute for Cancer Research (NICR) of Genoa. The HN-7 protocol compared neo-adjuvant chemotherapy (four cycles of vinblastine, 6 mg/m2 i.v. followed by bleomycin, 30 IU i.m. six hours later, day 1; methotrexate, 200 mg i.v., day 2; leucovorin, 45 mg orally, day 3) (VBM) followed by standard radiotherapy (70-75 Gy in 7-8 weeks) (55 patients) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation, 20 Gy each (61 patients). In the HN-8 protocol standard radiotherapy (77 patients) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin, 20 mg/m²/day and fluorouracil, 200 mg/m²/day, bolus, both given for five consecutive days (CF) instead of VBM (80 patients). A single database was created with the patients on the two protocols. Age at diagnosis, gender, site of the primary tumor, size of the primary, nodal involvement, performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method. The analyses were repeated including the treating institutions as a covariate (coordinating center versus others). Results: The multiple logistic regression analysis indicates that treatment (alternating more so than others, regardless of the chemotherapy regimen used) (P = 0.0001) is more likely to be associated with complete response. In addition, size of the primary tumor (P = 0.004), nodal involvement (P = 0.02) and performance status (P = 0.009) are prognostic variables affecting the probability of achieving a complete response. The Cox regression analysis indicates that treatment, performance status, size of the primary tumor, nodal involvement and, marginally, site of the primary tumor, are independent prognostic variables affecting the risk of death. When the radiation-alone therapy is adopted as the reference treatment, the relative risk of death is 0.58 (95% confidence interval (CI) 0.40-0.84) for alternating CF and radiation, 0.79 (95% CI 0.53-1.16) for alternating VBM and radiation and 1.30 (95% CI 0.89-1.92) for sequential VBM and radiation. When the treating institution is included in the model, a 34% increased risk of death (P = 0.04) is observed for patients treated outside the coordinating center. Conclusion: In our series of patients with advanced, unresectable SCC-HN, treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis. The role of the treating institution in the modulation of the treatment outcomes was also relevant.

Concomitant i.v. and oral clodronate in the relief of bone pain - a double-blind placebo-controlled study in patients with prostate cancer
T. Kylmälä¹, T. Taube², T.L.J. Tammela¹, L. Risteli³, J. Risteli³ and I. Elomaa^2
1Division of Urology. Department of Surgery, Tampere University Hospital, Finland; ²Department of Oncology, University of Helsinki, Finland; ³Departments of Medical Biochemistry and Clinical Chemistry, University of Oulu, Finland

Summary Summary. Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally randomized for treatment with clodronate or placebo. Clodronate treatment was started with 5 days intravenous administration (300 mg day¹) and followed by oral treatment (1.6 g ^day-1) for 12 months. Skeletal pain relief was only about 10% better in the clodronate than in the placebo group. The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only.

Only two of the limited number of studies on treatment of painful bone metastases due to prostate cancer with clodronate (Adami et al.. 1985; Adami et al., 1989; Elomaa et al., 1992; Vorreuther et al., 1992; Vorreuther, 1993; Kylmälä et al., 1994; Cresswell et al., 1995) have been placebo controlled (Adami et al., 1989; Elomaa et al., 1992). Adami and colleagues (1989) first showed, in 13 patients, that intravenous administration of clodronate was more effective in reducing bone pain than oral administration and that the effect lasted longer when intravenous administration was followed by oral treatment. We have shown that oral treatment with clodronate induces a moderate and transient pain relief in patients with hormone-refractory prostate cancer (Elomaa et al., 1992). It was concluded that the loss of effect resulted partly from dose reduction from 3.2 g to 1.6 g after the first month and partly due to the progression of disease despite basic cancer treatment.

In our recently published open pilot study (Kylmälä et al., 1994), more than half of the patients with prostate cancer and painful bone metastases reported pain relief after 6 days’ intravenous administration of clodronate (300 mg day-1), and the favourable effect lasted in all but three patients until the follow-up of 3 weeks, when the treatment was continued with oral administration (3.2 g day-¹).

The present study was conducted to see whether treatment with combined intravenous and oral administration of clodronate would induce a more rapid and effective pain relief than the treatment started with high oral dose. The study was prospective, randomized, double blinded and placebo controlled.

Conformal high dose rate iridium-192 boost brachytherapy in locally advanced prostate cancer: superior prostate-specific antigen response compared with external beam treatment
Jannifer S. Stromberg, MD, Alvaro A. Martinez, MD, FACR, Eric M. Horwitz, MD, Gary S. Gustafson, MD, Jose A. Gonzalez, MD, William F. Spencer, MD, Donald S. Brabbins, Md, Carl F. Dmuchowski, MPH, Jay B. Hollander, MD, Frank A. Vicini, MD, Royal Oak, Michigan

PURPOSE
Prostate-specific antigen levels are used to judge disease control of prostate cancer. No published data attest to the greater ability of conformal brachytherapy to control disease compared with conventional radiation at a single institution. This report compares the biochemical response rates in patients with stages T2b to T3c prostate cancer treated with conformal brachytherapy boost and external beam radiation with the rates in patients treated with conventional external radiation alone.

MATERIALS AND METHODS
From November 1991 through November 1995, 58 patients received 45.6 Gy pelvic external irradiation and three high dose rate iridium-192 conformal boost implants of 5.5 to 6.5 Gy each. They were compared with 278 similarly staged patients treated from January 1987 through December 1991 with external beam radiation to prostate-only fields (median dose 66.6 Gy). No patient received androgen deprivation. Patient outcome was analyzed for biochemical control. Biochemical failure was defined as a prostate-specific antigen level > 1.5 ng/mL and rising on two consecutive values. If serial posttreatment prostate-specific antigen levels were showing a continuous downward trend, failure was not scored.

RESULTS
Median follow-up was 43 months for the conventionally treated group and 26 months for the brachytherapy boost group. The median pretreatment prostate-specific antigen level was 14.3 ng/mL for the external-beam-radiation-alone group and 14.0 ng/mL for the brachytherapy boost group. The median Gleason scores were 6 and 7, respectively, for the two groups. The biochemical control rate was significantly higher in the brachytherapy boost treatment group. Three-year actuarial biochemical control rates were 85% versus 52% for the conformally and conventionally treated patients, respectively. In a multivariate analysis, the use of conformal brachytherapy boost and pretreatment prostate-specific antigen level were significant prognostic determinants of biochemical control. The 3-year actuarial rates of biochemical control for conformally versus conventionally treated patients, respectively, were 83% versus 72% for a pretreatment prostate-specific antigen level of 4.1 to 10.0 ng/mL, 85% versus 47% for a prostate-specific antigen of 10.1 to 20.0 ng/mL, and 89% versus 29% for prostate-specific antigen > 20 ng/mL. When the analysis was limited to patients in both groups with a minimum 12-month follow-up, the brachytherapy boost group continued to show a higher biochemical control rate compared with the conventional radiation group (3-year actuarial rates of 86% vs 53%).

DISCUSSION
These preliminary results show a significant improvement in the biochemical response rate with conformal boost brachytherapy and pelvic external radiation compared with conventional radiation alone. These results, coupled with our previously reported acceptable toxicity rates, support the use of this technique.

Cyclophosphamide, doxorubicin, vincristine, prednisone dose intensification with granulocyte colony-stimulating factor markedly depletes stem cell reserve for autologous bone marrow transplantation
By Arnold Freedman, Donna Neuberg, Peter Mauch, John Gribben, Robert Soiffer, Kenneth Anderson, Michael Robertson, David C. Fisher, Robert Schlossman, Mary Kroon, Catherine Rhuda, Caroline Kuhlman, Jerome Ritz and Lee Nadler

Hematopoietic growth factors allow dose escalation of chemotherapy. This approach may potentially reduce the quality and quantity of hematopoietic stem cells. The capacity of stem cells recovered after dose intensification to support myeloablative therapy is unknow. In patients with previously untreated advanced follicular lymphoma, trilineage hematopoietic engraftment was compared in two sequential trials of induction therapy (standard dose cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP] without growth factors or dose intensification CHOP supported by granulocyte colony-stimulating factor [G-CSF]) followed by identical myeloablative therapy and autologous stem cell support. Neutrophil, platelet, and red blood cell (RBC) engraftment were compared on days 100, 180, and 360 after stem cell reinfusion. Despite similar patient characteristics including reinfusion of comparable numbers of marrow mononuclear cells, after stem cell transplantation, a highly significant prolongation of neutrophil and platelet engraftment was seen in patients who received high dose CHOP and G-CSF in comparison to standard dose CHOP. These findings suggest that dose intensified chemotherapy and G-CSF recruited stem cells into a proliferative phase and that G-CSF allowed retreatment at a time when stem cells were susceptible to damage by cytotoxic therapy. Such inadequate hematologic engraftment after myeloablative therapy might be avoided by either shortening the time that growth factor support is administered, lengthening the interval between cycles, or attempting to repetitively harvest additional stem cells either from the marrow or peripheral blood. Therefore, intensification of chemotherapy with growth factor support must be used with caution if stem cells are to be used to support myeloablative therapy.

Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials
Chronic Myeloid Leukemia Trialists' Collaborative Group

Background: Several randomized clinical trials in chronic myeloid leukemia (CML) have reported better patient survival with interferon alfa (IFN a) than with standard chemotherapeutic agents, such as busulfan or hydroxyurea. However, the size and persistence of this survival benefit is uncertain. Our aim was to asses these reliably, both overall and in particular patient subgroups. Methods: We collaborated in a worldwide overview of all clinical trials in which patients with CML were randomly assigned to receive either IFN a as the main drug or standard chemotherapy. Trials were identified by electronic and hand searching of the medical literature and databases and by personal contact. Individual patient data were available for each of 1554 patients who had been randomly assigned to treatment in seven trials (German, Italian, British, French, Japanese, and "Benelux"). Intention-to-treat stratified logrank survival analyses were performed, reporting two-sided P values. Results: Almost all of the patients in these trials had disease with the Philadelphia chromosome abnormality. Among those who did, the regimens that involved IFN a produced a statistically significantly better survival than those involving either hydroxyurea (P = 0.001) or busulfan (P = 0.00007) alone. The 5-year survival rates were 57% with IFN a and 42% with chemotherapy, with an absolute difference of 15% (standard deviation = 3%; P < 0.00001). There were no trials or subgroups of patients in which the treatment difference was statistically significantly different from the average. Conclusion: For patients with Philadelphia chromosome-positive chronic myeloid leukemia, the inclusion of IFN a in the therapeutic regimen produced substantially better 5-year survival than standard chemotherapy alone.

Tobacco addiction: implications for treatment and cancer prevention
Paul M. Cinciripini, Stephen S. Hecht, Jack E. Henningfield, Marc W. Manley and Barnett S. Kramer

The American Society of Clinical Oncology and the National Cancer Institute convened a symposium in June 1996 on tobacco addiction. Additional support for the symposium was provided by the American Medical Women’s Association and the American Society of Preventive Oncology. The goals of this conference were to describe the burden and public health consequences of tobacco addiction, to describe the state of science for the treatment of nicotine dependence, and to explore new strategies to increase quit rates and to prevent the uptake of tobacco use. This article summarizes and integrates the meeting presentations on tobacco addiction and includes the topics of smoking prevalence; psychobiologic aspects of nicotine dependence; and implications for disease, treatment, and prevention. Comments on regulatory approaches and national strategies for reducing dependence are also summarized in presentations by Dr. David Kessler, former Food and Drug Administration Commissioner, and Dr. C. Everett Koop, former U.S. Surgeon General.

The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group
E. Vandenberghe¹, C. de Wolf-Peeter², G. Vaughan Hudson³, B. Vaughan Hudson³, S. Pittaluga², L. Anderson³ and D.C. Linch^{1, 3
1}Department of Haematology, University College London Medical School, London, ²Department of Haematopathology, KU Leuven, Belgium, and ³British National Lymphoma Investigation, UCL and CRC Cancer Trials Centre, Middlesex Hospital, London

Summary. Mantle cell lymphoma (MCL) was first described as a distinct biological entity on the basis of its association with the t (11:14) (q 13:q 32) resulting in over-expression of the cyclin D1 gene. Recognition of the morphological, immunophenotypic and clinical characteristics of MCL, has enabled the accurate diagnosis of this entity and appreciation of its poor prognosis. Most published series of patients with MCL have used anthracycline-containing regimens. In contrast the British National Lymphoma Investigation (BNLI) group have treated 65 patients with MCL with non-intensive 'low-grade lymphoma' therapy. The median overall survival of 57 months and progression-free survival of 24 months compares favourably with the more intensively treated series. Although the disease was generally more aggressive than other low-grade lymphomas, some patients were asymptomatic and had indolent disease. When compared to 1853 patients with non-MCL low-grade lymphomas entered on the BNLI database, patients were found on average to be older (P = 0.02), to have more extranodal disease (P < 0.00001), and a higher proportion to have a raised ESR (P = 0.02) and a low serum albumin (P = 0.002). Mitivariate analysis of significant prognostic markers in all BNLI low-grade lymphomas failed to identify MCL as an independent prognostic factor.

Paraproteinemia, plasmacytoma, myeloma and HIV infection
A.S. Fiorino¹ and B. Atac^{2, 3
1} 1Medical Scientist Training Program and ²2Department of Medicine, Albert Einstein College of Medicine; and ³ Department of Medicine, Jacobi Medical Center, Bronx, NY, USA.

We have identified by MEDLINE search the cases of gammaglobinopathy and plasma cell malignancy in HIV-positive patients reported in the English language literature. The average age at presentation among HIV-positive patients with plasma cell disorders is 33 years, far younger than the average age of presentation in the general population. Some of these patients present with transient paraproteinemias, while others have persistent paraproteins, which may or may not be associated with true plasma cell malignancies. In most cases in which it has been examined, the paraprotein contains high-titer anti-HIV activity. The presence of high-titer anti-HIV activity in the paraproteins of AIDS patients suggests that an antigen-driven process in response to HIV infection may contribute to the early development of plasma cell disorders in these patients. Recent work in plasma cell tumorigenesis has indicated that transformation at a single point in the B lymphocyte lineage can give rise to either lymphoma or myeloma, dependent upon environmental factors such as T cell function, which may be required for directing transformed lymphocytes from lymphoma and towards plasma cell differentiation. This may explain why B lineage oncogenesis in AIDS patients favors the development of lymphoma over that of myeloma.

Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia
S. Sacchi¹, H.M. Kantarjian¹, S. O'Brien¹, C. Koller¹, S. Pierce¹, S. Kornblau¹, E. Estey¹, M.J. Keating¹ and M. Talpaz²
Departments of ¹Hematology and ²Bioimmunotherapy, MD Anderson Cancer Center, Houston, TX, USA

The aim of this analysis was to evaluate the efficacy of alpha-interferon (a-IFN) regimens in late chronic phase (diagnosis > 12 months) chronic myelogenous leukemia (CP-CML). Long-term follow-up results were evaluated in 137 patients with Philadelphia chromosome (Ph)-positive late CP-CML. The a-IFN programs were sequential studies with human leukocyte a-IFN (seven patients), recombinant a-IFN alone (15 patients) or with IFN-g (29 patients), hydroxyurea (HU) (19 patients), or low-dose cytarabine (Ara-C) (67 patients). Overall, 57% of the patients achieved complete hematological response (CHR), and 7% obtained partial hematological response. Nineteen patients (15% of the 123 evaluable patients) had a cytogenetic response which was major (Ph-positive < 35%) in 10 patients (8%). A trend for better responses was observed with shorter disease duration. The median overall survival from start of therapy was 49 months, with an estimated 5-year survival rate of 41%. Some common pretreatment prognostic factors associated with response did not show statistical associations when applied in late CP-CML; however, characteristics such as smaller spleen size, and lower percentages of peripheral blood and marrow blasts and basophils were associated with better survival experience. When patients were subgrouped according to risk, no significant differences in the incidence of cytogenetic response and in survival outcomes were observed among various risk groups. This study confirms that a-IFN-based regimens have a modest activity in late CP-CML, and supports the need to develop investigational strategies aimed at improving patient prognosis in this phase.

Hodgkin's disease in childhood: a review
R. Beverly Raney, M.D.

The evolution of Hodgkin's disease (HD) in childhood is similar to its course in older patients, except that children < 10 years old have a better prognosis, perhaps because the favourable, lymphocyte-predominant form of the disease occurs more frequently in children than the unfavorable, lymphocyte-depleted form (1, 2). In the U.S., HD is the fifth most common malignant solid tumor in both white and black children < 15 years of age, after tumors of the brain, sympathetic nervous system, kidney, and soft tissues (3). In the U.S. and Europe, the incidence of HD is lower in children than in patients age 20 to 34 years; in general, this is true in Asia and Latin America, although the rise in incidence rates during the first two decades of life is smaller (4). These data have been interpreted to suggest the presence of an infectious agent in the etiology of the disease, but no proof of this theory has been found. However, there is increasing evidence for a role of the Epstein-Barr virus (EBV) in the pathogenesis of HD, especially in children < 10 years of age at diagnosis (5). EBV can be found in the typical and atypical Reed-Sternberg cells in patients with HD, especially in those with the pathologic subtype of mixed cellularity. EBV is only infrequently observed in the other subtypes, including nodular sclerosis (6, 7).

Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic-centrocytic lymphomas
Martin Stuschke, M.D., Angela Hoederath, M.D., Horst Sack, M.D., Richard P&oml;tter, M.D., Rolf-P. Müller, M.D., Ulrich Schulz, M.D., Johann Karstens, M.D., Hans-B. Makoski, M.D. for the Study Group NHL-frühe Stadien

Background. A prospective multicenter trial was performed to evaluate survival, patterns of relapse, and toxicity for clinically staged patients with lymph node centroblastic-centrocytic (cb/cc) lymphomas in Stages I-IIIA after large extended field irradiation (EFI) or total central lymphatic irradiation (TCLI). Methods. Between January 1986 and August 1993, 117 adults with clinical Stage I-IIIA lymph node cb/cc lymphoma (Kiel classification) were recruited. Patients in Stages I or II with mediastinal, hilar, periaortic, iliac, or mesenteric involvement and in Stage IIIA received TCLI, whereas patients with more peripherally located cb/cc lymphomas were treated with EFI. TCLI and EFI were administered to a total dose of 26 gray (Gy) with 2 Gy per daily fraction, with the exception of the whole abdomen, which was irradiated to a total dose of 25.5 Gy with 1.5 Gy per fraction. A boost of 10 Gy with 2 Gy per fraction was administered to enlarged and involved lymph nodes at the start of radiotherapy. Results. Sixty, 40, and 17 patients had Stage I, II, and limited IIIA disease (no bulk and less than 6 involved lymph node regions), respectively. Overall survival was 86% at 5 and 7 years; median follow-up was 68 months. The probabilities of relapse at any site, recurrences in lymph nodes, and in-field lymph node recurrences after TCLI were 17% in Stage I; 56%, 43%, and 40% in Stage II, respectively; and 44%, 35%, and 35% in Stage IIIA, respectively. The risk of disseminated extralymphatic relapses was 9% at 7 years. The most important adverse prognostic factor for in-field lymph node recurrences was a deviation of > 20% from the assigned total radiation dose. After EFI, patients in Stage I had a significantly lower risk of recurrences in adjuvant irradiated lymph node regions than in unirradiated lymph node regions. Acute toxicity of EFI and TCLI was moderate. Conclusions. In-field lymph node recurrences remained the main risk after TCLI, and a deviation of > 20% from the assigned radiation dose was the major risk factor for in-field recurrences. From these data, a total dose of 40-44 Gy in conventional fractionation for the treatment of macroscopic cb/cc lymphomas and 30 Gy for the treatment of subclinical disease is recommended. A randomized study comparing TCLI with EFI is now being organized by this group.

Primary extranodal non-Hodgkin's lymphomas. Part 1: gastrointestinal, cutaneous and genitourinary lymphoma
E. Zucca, E. Roggero, F. Bertoni and F. Cavalli
Servizio Oncologico Cantonale, Bellinzona, Switzerland

Key words: extranodal non-Hodgkin's lymphomas; gastrointestinal tract; genitourinary tract; MALT lymphoma; skin

Introduction
A substantial percentage of non-Hodgkin's lymphomas (NHL) arise from tissue other than lymph nodes and even from sites which normally contain no lymphoid tissue. These forms are referred to as primary extranodal lymphomas. At least one-fourth of the lymphomas are probably of extranodal origin [1]. Despite this relative prominence of extranodal presentations, the literature on their incidence and on most of the specific types and sites is scant and often contradictory. This is primarily because these tumours, numerous when considered together, are distributed so widely throughout the body that it is difficult to assemble adequate series of any given site. Moreover, for the most part it is necessary to resort to data from series assembled largely by selective referral; still only a minority of the published data have been collected prospectively from population-based registries [2, 3]

Moreover, the literature on extranodal lymphomas lacks uniformity in histopathological classification. Most of the historical series were published before the recognition of mucosa-associated lymphoid tissue (MALT) as the origin of many extranodal lymphomas and in general, classification of primary extranodal lymphomas was similar to that of nodal lymphomas, without consideration that their origin could be different. The first attempt to eliminate this problem was made only very recently with the proposal of the Revised European-American Classification of Lymphoid Neoplasms (REAL Classification) [4].

The definition of primary extranodal lymphoma, particularly in the presence of both nodal and extranodal disease, remains a controversial issue. Different criteria have been proposed in the past, most of them initially made for the gastrointestinal lymphomas [5-7] and later extrapolated to extranodal localizations in general [8]. Operationally, lymphomas can be considered as extranodal when, after routine staging procedures, there is either no or only 'minor' nodal involvement along with a clinically ‘dominant’ extranodal component, to which primary treatment must often be directed. More recently it has been proposed that minor nodal or dominant extranodal components can be defined, respectively, as < 25% or > 75% of the total tumour volume [3], but this proposal has not been widely accepted.

Another problem concerns the debate about whether tonsils and Waldeyer's ring should be considered as nodal or extranodal lymphoma sites [9]. In many respects they could be considered of nodal origin, but they have historically been included among the extranodal types [2, 3, 10-12) and, therefore, will be discussed in this review.