Responsável
Luiz Eduardo Atalécio

Esta seção tem por objetivo divulgar os resumos dos mais recentes artigos publicados na literatura mundial a respeito da epidemiologia, prevenção, diagnóstico, estadiamento, tratamento e prognóstico do câncer.

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Accelerated-interrupted radiation therapy given concurrently with chemotherapy for locally advanced non-small cell lung cancer
Munther Ajllouni, MD, Robert Chapman, MD, Jae Ho kim, MD, PhD, Detroit, Michigan

Purpose: To evaluate the efficacy of multidrug chemotherapy combined with accelerated radiation therapy in the treatment of localized but unresectable non-small cell lung cancer.

Patients and Methods: Between September 1990 and February 1993, 35 patients with Stage III (15 IIIA & 20 IIIB) non-small cell lung cancer were entered on a protocol using combined accelerated radiation therapy and chemotherapy. Radiation therapy consisted of 55.6 Gy in 30 fractions (1.8 Gy bid for 5 consecutive days given in 3 weeks [total of 15 days], every other week). Chemotherapy consisted of cisplatin (10 mg/m²), vinblastine (4 mg/m²), 6-thioguanine (40 mg bid), and 5-fluorouracil (400 mg/m² as continuous infusion) given concomitantly with radiation therapy. Approximately 3 weeks following completion of radiation therapy, two cycles of consolidation chemotherapy were given, consisting of two doses of cisplatin (120 mg/m²) 4 weeks apart and six doses of vinblastine (4 mg/m²) given on two consecutive days every other weeks for weeks.

Results: Six patients were still at last follow-up; for them the median follow-up time is 47 months (range, 39-55.8). The median survival time is 17.5 months. The 1-, 2-, 3-and 4.5-year survival rates are 69%, 37%, 20% and 17%, respectively. Overall response rate is 63%, with 51,5% partial response and 11,5% complete response rates. Esophagitis occurred as follows: Grade 4 = 0, Grade 3 = 1, Grade = 2 = 6, and Grade 1 = 13. No patient developed Grade 3 or 4 acute respiratory toxicity. Significant hematologic toxicity occurred as follows: 37% Grade 3 and 31% Grade 4 leukopenia. Radiation pneumonia occurred in two patients.

Discussion: The regimen tested in this protocol appears to be very well tolerated with minimal pulmonary or esophageal toxicity. This, coupled with the shortened course of radiation therapy and the ability to deliver the combined radiation and chemotherapy portion of the treatment on an outpatient basis most of the time, has made multimodality treatment for this malignancy much easier and more convenient for patients. In addition, the favorable survival in this group of patients with locally advanced disease is very encouraging and warrants further study.

Tobacco litigation as cancer prevention: dealing with the devil
George J. Annas, J.D., M.P.H.

Tobacco companies have come to personify the devil, and strategies to exorcise tobacco smoking from the United Stated proliferate. Tobacco’s demonic status is even reflected in popular fiction. John Grisham’s latest bestseller, The Runaway Jury, for examples, is a broadside attack on tobacco companies. He opens the book by noting that tobacco companies "had been thoroughly isolated and vilified by consumer groups, doctors, even politicians." This was bad, but it was getting even worse: "Now the lawyers were after them."

Physicians often see trial lawyers as predators, but choosing sides between lawyers and big tobacco has, at least recently, seemed easy. The American Medical Association (AMA), for example, now endorses "all avenues" of litigation against the tobacco companies as a public health strategy. As New York Times reporter Phillip J. Hilts puts it in a recently published book, "The natural end for a tangle like the tobacco wars is in court."

Lawsuits against tobacco companies are not a new phenomenon, but until 1996 they seemed singularly impotent. Chroniclers of tobacco litigation identify three waves of litigation. The first dates from the time medical research first demonstrated the risks of cancer from smoking and continued until the early 1970s (1954 to 1973). The second wave (1983 to1992) began in the early 1980s and ended with the dropping of the Cipollone case (the subject of a previous column). Tobacco companies paid nothing to claimants in any of these lawsuits, ultimately winning them all by relying on three arguments: smoking is the result of a free choice, there is no conclusive proof that tobacco causes disease, and the industry supports research on the effects of smoking on health. The third wave, which dates from 1994, is seen as much more likely to succeed, because of the discovery of vast array of previously secret documents that undercut the industry’s own arguments, including documents indicating that the industry knew nicotine was addictive and used this knowledge to hook users. A new study that shows how a tar ingredient, benzo(a) pyrene, causes cancer by affecting the P53 gene is prompting tobacco companies to rethink their position on causation. Moreover, while plaintiff lawyers had previously been totally outgunned financially by tobacco companies willing to pay virtually any price not to lose a case, third-wave cases have been brought by teams of law firms and by state attorneys general with the help of private lawyers. The playing field had been leveled to such an extent that discussions have begun on how Congress might act to settle all tobacco lawsuits in a fair manner.

Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer
Michael Fanucchi, M.D., John Glaspy, M.D., Jeffrey Crawford, M.D., Jennifer Garst, M.D., Robert Figlin, M.D., William Sheridan, M.B., B.S., Dora Menchaca, PhD., Dianne Tomita, M.P.H., Howard Ozer, M.D., PhD, Laurence Harker, M.D.

Background: Polyethylene glycol (PEG)-conjugated recombinated human megakaryocyte growth and development factor (MGDF, also known as PEG-rHuMGDF), a recombinant molecule related to thrombopoietin, specifically stimulates megakaryopoiesis and platelet production and reduces the severity of thrombocytopenia in animals receiving myelosuppressive chemotherapy.

Methods: We conducted a randomized, double-blind, placebo-controlled dose-escalation study of MGDF in 53 patients with lung cancer who were treated with carboplatin and paclitaxel. The patients were randomly assigned in blocks of 4 in a 1:3 ratio to receive either placebo or MGDF (0.03, 0.1, 1.0, 3.0 or 5.0 µg per kilogram of body weight per day), injected subcutaneously. No other marrow-active cytokines were given.

Result: In the 38 patients who received MGDF after chemotherapy, the median nadir platelet count was 188,000 per cubic milimeter (range, 68,000 to 373,000), as compared with 111,000 per cubic millimeter (range, 21,000 to 307,000) in 12 patients receiving placebo (P = 0.013). The platelet count recovered to base-line levels in 14 days in the treated patients as compared with more than 21 days in those receiving placebo (P < 0.001). Among all 40 patients treated with MGDF, 1 had deep venous thrombosis and pulmonary embolism, and another had superficial thrombophlebitis.

Conclusions: MGDF has potent stimulatory effects on platelet production in patients with chemotherapy-induced thrombocytopenia.

Occupational exposure to blood among medical students
P.M. Tereskerz, R.D. Pearson, J. Jagger

One of the most serious threats medical students face during their clinical training is the possibility of exposure to blood-borne pathogens, with the attendant risk of infection with the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Yet the problem of exposure to contaminated blood among the estimated 50,000 medical students in the United States, about half of whom are receiving clinical training in the nation’s 126 medical schools at a given time, has received little attention.

The risk of percutaneous injury to health care workers has been well documented. It is estimated that the 4.4 million health care workers in the United States receive approximately 800,000 needle sticks and other injuries from sharp objects annually. An estimated 16,000 of these objects are contaminated with HIV, and even more are contaminated with HBV or HCV. There are limited data suggesting that medical students receive percutaneous injuries as often or more often than health care workers, with most injuries occurring from needles used to draw blood or to suture. Koenig and Chu reported that 48 percent of all graduating medical students recalled being exposed at least once to potentially infectious body fluids during their last two years of medical school. Fifty-seven percent of these exposures were skin punctures. Another recent survey indicated that 27 percent of medical students undertaking clinical rotations had been injured by sharp objects or had had mucocutaneous exposure to patients’ body fluids in the previous six months.

Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small-cell lung cancer
Raymond P. Abratt, Werner R. Bezwoda, Louis Goedhals, Dayle J. Hacking

Purpose: The aim of this study was to examine the efficacy of a regimen of initial gemcitabine followed by cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

Patients and Methods: Fifty-three patients (36 men and 17 women; age range, 35 to 74 years) were enrolled. Patients had bidimensionally measurable disease. Gemcitabine (phase-specific agent) was administered on days 1, 8, and 15 at a dose of 1,000 mg/m². Cisplatin (cycle-specific agent) was administered on day 15 (100 mg/m²). Chemotherapy was administered in 28-day cycles.

Results: Of 53 patients enrolled, 50 were assessable for response. The overall response rate was 52%. There were two complete responses (4%) and 24 partial responses (48%). The median survival duration was 13 months and the 1-year survival rate was 61%. The regimen was generally well tolerated. World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 38.8% and 19.2% of patients, respectively. Grade 3 and 4 thrombocytopenia occurred in 13.3% and 7.7% of patients, respectively. Most patients experienced mild nausea and vomiting. Few patients had hair loss and oral toxicity was mild. Relatively few patients required dose modifications for any of the three weekly doses of chemotherapy. For the first two cycles of chemotherapy, the dose-intensity per infusion was 947 mg/m² for gemcitabine and 85 mg/m² for cisplatin.

Conclusion: This regimen of gemcitabine and cisplatin was effective, with high response and survival rates and few dosage modification during its administration. Prospective randomized studies with other cisplatin-based combination chemotherapy regimens are indicated.

Combined carboplatin and cisplatin therapy in patients with advanced non-small cell lung cancer
Ryoichi Nakanishi, MD, Toru Kume, MD, Tetsuya Mitsudomi, MD, Takashi Yoshimatsu, MD, Toshihiro Osaki, MD, Hiroyuki Tokunaga, MD, Kosei Yasumoto, MD

Combining cisplatin and carboplatin may eliminate some of the toxic effects of each agent and permit the use of higher doses, because these agents have different pharmacodynamics and dose-limiting toxicities. We investigated the safety and efficacy of these agents in combination. The toxicity profile was evaluated in a Phase I trial in 18 patients with advanced non-small cell lung cancer (NSCLC). Carboplatin was administered in doses ranging from 200 to 400 mg/m² on day 1 and cisplatin at a dose of 80 mg/m² on day 3. Only one cycle of chemotherapy was administered. Thrombocytopenia was the dose-limiting toxic effect. The maximal tolerated dose of carboplatin was 350 mg/m². We then investigated the efficacy of the optimal dose of this combined chemotherapy in a Phase II trial in 13 patients. We used a carboplatin dose of 300 mg/m² for safety in the Phase II trial. Three of 13 patients developed grade 3-4 hematologic toxicity, which was improved without major complications. A partial response was observed in 5 of 13 patients (38.5%). Combination chemotherapy with carboplatin (day 1,300 mg/m²) and cisplatin (day 3,80 mg/m²) showed promising effects in patients with advanced NSCLC.

Dose-intense therapy with etoposide, ifosfamide, cisplatin, and epirubicin (VIP-E) in 100 consecutive patients with limited-and extensive-disease small-cell lung cancer
S. Fetscher¹, W. Brugger⁴, R. Engelhardt¹, L. Kanz⁴, J. Hasse², H. Frommhold³, M. Wenger¹, W. Lange¹, R. Mertelsmann¹

¹Division of Hematology and Oncology, Department of Internal Medicine;
²Department of Thoracic Surgery; ³Department of Radiation Therapy, University of Freiburg Medical Center, Freiburg im Breisgau;
⁴Division of Hematology and Oncology, Department of Internal Medicine, University of Tübingen Medical Center, Tübingen am Neckar, Germany

Background: We conducted a phase I/II trial to assess the feasibility and activity of VIP-E chemotherapy in small-cell lung cancer. End-points were treatment-related morbidity and mortality, response to treatment, duration of response, and survival.

Patients and methods: Two cycles of combination chemotherapy followed by granulocyte colony-stimulating factor (G-CSF) were given at a dose of etoposide (500 mg/m²), ifosfamide (4000 mg/m²), cisplatin (50 mg/m²), and epirubicin (50 mg/m²) to 100 consecutive patients with SCLC. Thirty patients (19 with LD, and 11 with ED SCLC) proceeded to VIC-E high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) at a cumulative dose of etoposide 1500 mg/m², ifosfamide 12,000 mg/m², carboplatin 750 mg/m² and epirubicin 150 mg/m². Surgical resection of primary tumor was attempted at the earliest feasible point. Thoracic irradiation was given after completion of chemotherapy.

Results of conventional-dose VIP E: 97 patients were evaluable for response. Objective response rate was 81% in LD-SCLC (33% CR, 48% PR: excluding patients in surgical CR) and 77% in ED-SCLC (18% CR, 58% PR). Treatment mortality was 2%. Median survival was 19 months in LD-SCLC and 6 months in ED-SCLC. Two-year survival was 36% in LD and 0% in ED SCLC.

Results of high-dose VIC-E: All 30 patients improved on or maintained prior responses. Four patients (13%) died of treatment-related complications. Median survival was 26 months in LD-SCLC and 8 months in ED-SCLC. Two year survival was 53% in LD and 9% in ED SCLC.

Conclusion: VIP-E chemotherapy is an effective induction therapy for SCLC. Compared with traditional protocols such as ACO or carboplatin/etoposide, response rates are slightly improved, while survival is not different. In the LD SCLC subgroup, high-dose chemotherapy improved response rates and survival, especially for patients in surgical CR prior to high-dose therapy. In ED SCLC, however, higher response-rates did not translate into improved survival. Selected LD-SCLC patients with good partial or complete remissions after prior therapy may benefit from HDC and PBSCT.

Anxiety and depression in hospitalized patients with cancer: agreement in patient-staff dyads
Claudia Lampic, MSc, Louise von Essen, PhD, Viveca Widmark Peterson, R.N.T., Gunnel Larsson, R.N., Per-Olow Sjödén, PhD

Patient and staff perceptions of patient anxiety and depression were determined in 53 dyads of hospitalized cancer patients and their nursing staff. Patient anxiety and depression were assessed with the Hospital Anxiety and Depression Scale. In addition, anxiety was measured by a numerical (0-10) scale. A staff person who had been caring for a certain patient the previous 3 days assessed that patient’s anxiety and depression with staff versions of the same instruments. For one subsample (n = 18), staff were also asked to estimate their own hypothetical anxiety were they to have the same disease as the patient. Results indicate that staff overestimated patient anxiety systematically and showed limited ability to adequately assess patient anxiety and depression in terms of rank. Patients and staff agreed about individual patients’ levels of anxiety and depression only to a limited degree. Discrepancies between patient and staff ratings of patient anxiety predominantly concerned patients reporting low anxiety levels. Several explanations for these findings are discussed. One possible explanation, the "requirement of mourning" hypothesis, is supported by our findings that staff estimation of patient anxiety was strongly associated with their estimation of their own hypothetical anxiety if they were to be in the patient’s situation.

Complications of an implantable venous access device (Port-Cath®) during intermittent continuous infusion of chemotherapy
R.L. Poorter¹, F.N. Lauw^{1, 2}, W.A. Bemelman², P.J.M. Bakker¹, C.W. Taat², C.H.N. Veenhof¹

¹Department of Medical Oncology; and
²Department of Surgery, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands

In 149 patients, treated with intermittent continuous infusion of different chemotherapeutic agents, 169 Port-a-Caths®® were implanted by qualified surgeons and residents in training. The peri-and postoperative complications of implantation of the Port-a-Cath® system and the complications during treatment were retrospectively analysed. The Port-a-Cath® was in situ for a total of 36247 days (median 181, range 1-1332). Of the 169 catheters, major complications occurred during treatment, with infection in 4 patients (2.4%), occlusion in 3 (1.8%), thrombosis in 8 (4.7%), extravasation in 8 (4.7%) and migration in 3 (1.8%). The peri- and postoperative complication rate was low, although pneumothorax occurred in 6 patients (3.6%). In 25 patients (14.8%) the Port-a-Cath® had to be explanted due to complications. It can be concluded that continuous infusion of chemotherapy via a Port-a-Cath® system is a relatively safe procedure, although major complications do occur. The experience of the surgeon could not be related to the complications.

Guidelines on diet, nutrition, and cancer prevention: reducing the risk of cancer with healthy food choices and physical activity
American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention
The American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention: Marion Nestle, PhD, MPH (Chair); Dileep G. Bal, MD, MS, MPH, Diane F. Birt, PhD, Gladys Block, PhD; Tim Byers, MD, MPH; Susan Foerster, MPH, RD, Peter Greenwald, MD, DrPH, Ervin J. Hawrylewicz, PhD, Brian E. Henderson, MD, David Hunter, ScD, Lenore A. Kohlmeier, PhD; David Kritchevsky; PhD, Shiriki K. Kumanyika, PhD; MPH, RD; Lawrence Kushi, ScD; Bonnie F. Liebman, MS; Robert Russell, MD; Henry Thompson, PhD; David F. Williamson, PhD; MS, American Cancer Society Staff Participants: Lynne Camoosa; Steeve Dickinson; Nancy Hailpern; Clark Heath, MD; Roberta Moss, MPH; Mary C.O.’Connell; Billie Parker; Amy Stone; Michael Thun, MD; Allen Vegotsky, PhD

The importance of nutrition in cancer prevention. The American Cancer Society publishes nutrition guidelines to advise the public about dietary practices that reduce cancer risk. These guidelines are developed by expert advisory committees and are based on existing evidence that relates diet and nutrition to cancer risk in human population studies as well as in laboratory experiments.

This evidence suggests that about one third of the 500,000 cancer deaths that occur in the United States each year is due to dietary factors. Another third is due to cigarette smoking. Therefore, for the large majority of Americans who do not smoke cigarettes, dietary choices and physical activity become the most important modifiable determinants of cancer risk. The evidence also indicates that although genetics is a factor in the development of cancer, cancer cannot be explained by heredity alone. Behavioral factors such as cigarette smoking, dietary choices, and physical activity modify the risk of cancer at all stages of its development. The introduction of healthful diet and exercise practices at any time from childhood to old age promote health and reduce cancer risk.

On the basis of its review of the scientific evidence, the American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention reaffirms previous conclusions of the Society that dietary practices and physical activity - along with smoking cessation, avoidance of occupational carcinogens, and early detection - are important factors in the prevention of cancer and cancer death.

Many dietary factors can affect cancer risk: types of foods, food preparation methods, portion sizes, food variety, and overall caloric balance. Cancer risk can be reduce by an overall dietary pattern that includes a high proportion of plant foods (fruits, vegetables, grains, and beans); limited amounts of meat, dairy, and other high-fat foods; and a balance of caloric intake and physical activity.

Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis
Jacques Cornuz, MD, MPH, Seteven D. Pearson, MD, MSc, Mark A. Creager, MD, E. Francis Cook, ScD, Lee Goldman, MD, MPH

Background: The relation between thrombosis and cancer is well documented, but the clinical evaluation appropriate for detecting underlying cancer in patients with deep venous thrombosis remains unknown.

Objectives: To 1) determine the appropriate initial evaluation for cancer in patients with idiopathic deeps venous thrombosis and 2) estimate the incidence of subsequently diagnosed cancer in patients who were not found to have cancer when deep venous thrombosis was diagnosed.

Design: Retrospective cohort study.

Setting: Urban, tertiary care teaching hospital.

Patients: 986 consecutive patients (637 women and 349 men: mean age ± SD, 53 ± 17 years) who had no risk factors for venous disease and had venous ultrasonography because idiopathic deep venous thrombosis was suspected.

Measurements: Initial clinical evaluation was assessed by using chart review. The incidence of cancer at a median of 34 months after diagnosis of deep venous thrombosis was obtained through hospital chart review (38%), computerized record extraction (54%), mailed questionnaires (6%), telephone interviews (1%), or a death registry (1%).

Results: Deep venous thrombosis was diagnosed in 142 patients (14%); 136 of the 142 were hospitalized. Cancer was diagnosed in 16 of these 136 patients (12%) during the index hospitalization. All 16 of these patients had one or more abnormalities on at least one of the four components of the clinical examination: history, physical examination, basic laboratory testing, or chest radiography. The probability of detecting cancer increased as the number of findings suggestive of cancer on the four components of the clinical evaluation increased. Cancer was diagnosed in none of the 56 patients with deep venous thrombosis who did not have findings on the clinical evaluation. The probability of cancer-free survival during follow-up (median, 34 months) was similar in patients with (3 of 122[2.5%]) and without (23 of 844 [2.7%]) deep venous thrombosis and in the age and sex-matched U.S. population.

Conclusions: A clinical evaluation that includes a comprehensive medical history, physical examination, routine laboratory testing, and chest radiography seems to be appropriate for detecting cancer in these patients. Additional testing should be guided by any abnormalities detected by this clinical evaluation.

Tumor antigens and tumor vaccines: peptides as immunogens
Craig L., Slingluff JR, MD
From the Department of Surgery, Division of Surgical Oncology, University of Virginia Health Sciences Center, Charlottesville, Virginia

Tumor antigens recognized by human T lymphocytes (CTL) have been identified for multiple types of solid tumors. These include both shared and unique antigens. Unique antigens are those expressed uniquely by one patient’s tumor, and shared antigens are those present on tumor cells from many different patients. Many of the shared antigens are derived from tissue-specific differentiation antigens, oncogenes, or a set of antigens expressed only in tumors or in testis. In addition to advances in understanding tumor antigens that stimulate CTL and T-helper cell responses, there have been advances in understanding immunity in general, including the characterization of cytokines, the recognition of the dendritic cell as an optimal antigen-presenting cell (APC), and the characterization of costimulatory molecules as critical components of antigen presentation. Together, these developments have breathed new life into tumor immunology, and they promise to lead to a new generation of peptide- and cell-based tumor vaccines.

Cancer undefeated
John C. Bailar III, MD, PhD, Heather L. Gornik, MHS

Background: Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality. We assessed overall progress against cancer in the United States from 1970 through 1994 by analyzing changes in age-adjusted mortality rates.

Methods: We obtained from the National Center for Health Statistics data on all deaths from cancer and from cancer at specific sites, as well as on deaths due to cancer according to age, race, and sex, for the years 1970 through 1994. We computed age-speficic mortality rates and adjusted them to the age distribution of the U.S. population in 1990.

Results: Age-adjusted mortality due to cancer in 1994 (200.9 per 100,000 population) was 6.0 percent higher than the rate in 1970 (189.6 per 100,000). After decades of steady increases, the age-adjusted mortality due to all malignant neoplasms plateaued, then decreased by 1.0 percent from 1991 to 1994. The decline in mortality due to cancer was greatest among black males and among persons under 55 years of age. Mortality among white males 55 or older has also declined recently. These trends reflect a combination of changes in death rates from speficic types of cancer, with important declines due to reduced cigarette smoking and improved screening and a mixture of increases and decreases in the incidence of types of cancer not closely related to tobacco use.

Conclusions: The war against cancer is far from over. Observed changes in mortality due to cancer primarily reflect changing incidence or early detection. The effect of new treatments for cancer on mortality has been largely disappointing. The most promising approach to the control of cancer is a national commitment to prevention, with a concomitant rebalancing of the focus and funding of research.

Risk of cancer and exposure to gasoline vapors
Elsebeth Lynge, Aage Andersen, Ralph Nilsson, Lotti Barlow, Eero Pukkala, Rolf Nordlinder, Paolo Boffetta, Philippe Grandjean, Pirjo Heikkilä, Lars-Gunnar Hörte, Robert Jakobsson, Ingvar Lundberg, Bente Moen, Timo Partanen, Trond Riise

Until the introduction of self-service around 1970, service station workers in the Nordic countries were exposed to gasoline vapors. Based on measurements reported in the literature, the 8-hour time-weighted average benzene exposure was estimated to be in the range of 0.5-1 mg/m³. We studied the cancer incidence in a cohort of 19,000 service station workers from Denmark, Norway, Sweden, and Finland. They were identified from the 1970 censuses and followed through 20 years, where 1,300 incident cancers were observed. National incidence rates were used for comparison. The incidence was not increased for leukemia (observed = 28, standardized incidence ratio (SIR) = 0.9%, 95% confidence interval (CI) 0.6-1.3) nor for acute myeloid leukemia (observed = 13, SIR = 1.3, 95% CI 0.7-2.1). The incidence was slightly elevated for kidney cancer (observed = 57, SIR = 1.3, 95% CI 1.0-1.7) and for pharyngeal, laryngeal, and lung cancer. A 3.5-fold risk of nasal cancer was found (observed = 12, SIR = 3.5, 95% CI 1.8-6.1). This cohort exposed to gasoline vapors with benzene levels estimated to be 0.5-1 mg/m³ showed no excess risk of leukemia or acute myeloid leukemia, a 30% elevated risk of kidney cancer, and a previously unnoticed risk of nasal cancer.

Use of multiple primary cancers to indicate associations between smoking and cancer incidence: an analysis of 500,000 cancer cases diagnosed in Norway during 1953-93
Anders Engeland¹, Tone BjØrge^{1, 2}, Tor Haldorsen¹, Steinar Tretli^1
1Cancer Registry of Norway, Institute for Epidemiological Cancer Research, Oslo, Norway;
²Department of Gynecologic Oncology, The Norwegian Radium Hospital, Oslo, Norway

The occurrence of multiple primary cancers is relatively rare, but may provide indications of common or opposite risk factors for different types of cancer. In the present study, the occurrence of multiple primary cancers was used to indicate possible associations between smoking and the incidence of cancers other than those generally accepted as smoking-associated. All cancer cases in persons above the age of 30, registered at the population-based Cancer Registry of Norway (1953-1993), were used in the analysis. For each type of cancer, the observed occurrence of smoking-associated cancers in the patients was compared with the expected occurrence if the patients had the same risk as the general population. Similar comparisons were made for the occurrence of other cancers in patients with a smoking-associated cancer. The results were presented as standardized incidence ratio (SIR), the ratio of the observed and the expected numbers of cases. The results indicated that uterine cervical cancer may share some important risk factor(s) with the cancers generally accepted as smoking-associated. This is in accordance with the literature, where an association between smoking and uterine cervical cancer has been found consistently. In addition, the results for liver cancer and leukemia indicated that these types of cancer also share some risk factor(s) with the smoking-associated cancers.

Estimating the prevalence of cancer in the United States
Anthony P. Polednak, PhD

Background: Few reports have estimated the prevalence of persons in the U.S. ever diagnosed with invasive cancer.

Methods: The Connecticut Tumor Registry was used to identify all Connecticut residents ever diagnosed (1935-1994) with invasive cancer who were known to be alive in 1994. Estimated prevalence rates for Connecticut were compared with those for 1982, and were applied to the total U.S. population for selected years.

Results: Some 95,361 persons ever diagnosed with invasive cancer(s) were confirmed as being alive at the end of 1994. The age-standardized prevalence rate had increased by 40% in males and 13% in females since 1982, due in part to large increases for breast, prostate, and (in females) lung carcinoma. Using the data for Connecticut, an estimated 7.1 million Americans in 1995 had ever been diagnosed with invasive cancer, projected numbers were 7.7 million for 2000 and 13.2 million for 2030.

Conclusions: The prevalence of persons ever diagnosed with invasive cancer could increase considerably in the coming decades, and numbers for elderly males could surpass those for elderly females by 2020. Although projections must be interpreted with caution, these data emphasize the need for primary prevention of cancer and for studies of cancer survivors.

Comparative clinical efficacy and safety of a novel controlled-release oxycodone formulation and controlled-release hydromorphone in the treatment of cancer pain
Neil A. Hagen, MD, FRCP, Najil Babul, Pharm.D

Background: The use of oxycodone to treat chronic cancer pain had been hampered by its short elimination half-life, which necessitates administration every 4 hours. This study compared the clinical efficay and safety of a novel oxycodone formulation with that of hydromorphone in the treatment of cancer pain.

Methods: In a double-blind crossover study, 44 patients with stable cancer pain were randomized to controlled-release oxycodone or controlled-release hydromorphone, each given every 12 hours for 7 days. Pain intensity, nausea, and sedation were assessed by patients four times daily, and breakthrough analgesia was recorded.

Results: Thirty-one patients completed the study (18 women, 13 men: mean age, 56 ± 3 years) and received a final controlled-release dose of 124 ± 22 mg per day and a final controlled-release hydromorphone dose of 30 ± 6 mg per day. There were no significant differences between treatments in overall Visual Analogue Scale (VAS) pain intensity (VAS 28 ± 4 mm vs. 31 ± 4 mm), categorical pain intensity (1.4 ± 0.1 vs. 1.5 ± 0.1), daily rescue analgesic consumption (1.4 ± 0.3 vs. 1.6 ± 0.3), sedation scores (24 ± 4 mm vs. 18 ± 3 mm), nausea scores (15 ± 3 mm vs. 13 ± 3 mm), or patient preference. Two patients experienced hallucination on controlled-release hydromorphone, but none did while receiving controlled-release oxycodone.

Conclusions: Controlled-release oxycodone demonstrated excellent pharmacodynamic characteristics, analgesic efficacy, and safety as compared with controlled-release hydromorphone and represents an important new therapeutic option for cancer pain management,

Large trials vs. Meta-analysis of smaller trials. How do their results compare?
Joseph C. Cappelleri, PhD, MPH, John P.A. Ioannidis, MD, Christopher H. Schmid, PhD, Sarah D. de Ferranti, MD, MPH, Michael Aubert, Thomas C. Chalmers, MD†; Joseph Lau, MD

Objective: To evaluate the results of large clinical trials vs the pooled results of smaller trials.

Data identification: Meta-analyses with at least 1 "large" study were identified from the Cochrane Pregnancy and Childbirth Database and from MEDLINE (1966-1995).

Study selection: We used a sample size approach to select 79 meta-analyses with at least 1 large study of 1000 or more patients. We used a statistical power approach to select 61 meta-analyses with at least 1 large study based on statistical power considerations.

Data extraction: The outcome of interest for each meta-analysis was the primary one stated in the original publication or, when not clearly speficied, was decided on clinically.

Data synthesis: By random effects calculations, we found agreement between large and smaller trials in 90% of the meta-analyses selected by the sample size approach and in 82% of the meta-analyses selected by the statistical power approach. Twice as many disagreements appeared when the variability among large studies and among smaller studies was not considered (ie, fixed effects calculations). Of the 15 disagreements between results of large and smaller trials using the random effects model, plausible explanations were identified in 10 meta-analyses: 5 with differences in the control rate of events between large and smaller trials, 4 with speficic protocol or study differences, and 1 with potential publication bias. Two other disagreements were not clinically important, and tentative reasons could be identified for 2 of the remaining 3 disagreements.

Conclusions: Results of smaller studies are usually compatible with the results of large studies, but discrepancies do occur event then the diversity among both large studies and smaller studies is considered. Clinically important differences without a potential explanation are extremely uncommon. Future research should further examine sources of heterogeneity between the results of large and smaller trials.

Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers
Daniel F. Hayes, Robert C. Bast, Christopher E. Desch, Herbert Fritscher Jr., Nancy E. Kemeny, J. Milburn Jessup, Gershon Y. Locker, John S. Macdonald, Robert G. Mennel, Larry Norton, Peter Ravdin, Sheila Taube, Rodger J. Winn

Introduction of tumor markers into routine clinical practice has been poorly controlled, with few criteria or guidelines as to how such markers should be used. We propose a Tumor Marker Utility Grading System (TMUGS) to evaluate the clinical utility of tumor markers and to establish an investigational agenda for evaluation of new tumor markers. A Tumor Marker Utility Worksheet has been designed. The initial portion of this worksheet is used to clarify the precise characteristics of the marker in question. These characteristics include the marker designation, the molecule and/or substance and the relevant alteration from normalcy, the assay format and reagents, the specimen type, and the neoplastic disease for which the marker is being evaluated. To determine the clinical utility of each marker, one of several uses must be designated, including risk assessment, screening, differential diagnosis, prognosis, and monitoring clinical course. For each of these uses, associations between marker assay results and expected biologic process and end poitns must be determined. However, knowledge of tumor marker data should contribute to a decision in practice that results in a more favorable clinical outcome for the patient, including increased overall survival, increased disease-free survival, improvement in quality of life, or reduction in cost of care. Semiquantitative utility scales have been developed for each end point. The only markers recommended for use in routine clinical practice are those that are assigned utility scores of "++" or "+++" on a 6-point scale (ranging from 0 to +++) in the categories relative to more favorable clinical outcomes. Each utility score assignment should be supported by documentation of the level of evidence used to evaluate the marker. TMUGS will establish a standardized analytic technique to evaluate clinical utility of known and future tumor markers. It should result in improved patient outcomes and more cost-efficient investigation and application of tumor markers.

Continuous infusion of 5-fluorouracil and low dose cisplatin infusion for the treatment of advanced and recurrent gastric adenocarcinoma
Yong-Suk Chung, MD, Yoshito Yamashita, MD, Tohru Inoue, MD, Tasuku Matsuoka, MD, Bunzo Nakata, MD, Naoyoshi Onoda, MD, Kiyoshi Maeda, MD, Tetsuji Sawada, MD, Yasuyuki Kato, MD, tetsuhiko Shirasaka, PhD, Michio Sowa, MD

Background: Several chemotherapy studies have suggested that continuous infusion of 5-fluorouracil (5-FU) is more effective than bolus 5-FU. In addition, 5-FU and cis-Diamminedichloroplatinum-II (cisplatin) in combination have been shown to have synergistic cytotoxicity against several human neoplasms. In this study, the authors evaluated the efficacy and toxicity of continuous infusion of 5-FU and low dose cisplatin infusion (FP therapy) in the treatment of advanced and recurrent gastric adenocarcinoma. The relationship between the response to FP therapy and several factors was also examined.

Methods: A total of 26 patients fulfilling standard eligibility criteria were enrolled in the trial. FP therapy consisted of 5-FU (350 mg/m²/day every day by continuous infusion) and cisplatin (7.5 mg/m²/day in 100 mL of normal saline infused over 1 hour on days 1-5 every week) for weeks.

Results: A complete response was observed in 2 cases and a partial response in 11 cases, for an overall response rate of 50%. Patients with good performance status (PS) (0-1) and differentiated histologic type showed higher response rates (50.0% and 63.6%, respectively) than patients with poor PS (2 or 3) and undifferentiated histologic type (28.6% and 35.3%, respectively), although there were no significant differences. Patients with low serum levels of immunosuppressive acidic protein (IAP) showed a significantly higher response rate (71.4%) than those with high IAP levels (0%). Toxic effects included leukopenia, thrombocytopenia, nausea, and vomiting; these were not life-threatening and did not require treatment interruption.

Conclusions: FP therapy is a promising regimen for patients with advanced and recurrent gastric adenocarcinoma. Serum levels of IAP may predict chemosensitivity.

Background: The major advantage of diagnostic laparoscopy for patients with a gastrointestinal tumor is the prevention of unnecessary explorative laparotomies. However, it is doubtful whether this procedure also prevents late laparotomies that are necessary for palliative treatment during follow-up.

Methods: From January 1992 to July 1995, 233 consecutive patients with gastrointestinal malignancies underwent laparoscopy and laparoscopic ultrasonography after routine diagnostic procedures had shown potential curative disease.

Results: After diagnostic laparoscopy, laparotomy was not performed in 21% of all patients (47 of 226) because of histologicaly proven, unresectable, mainly metastatic disease; 6% has esophageal tumors (4 to 64 patients), 43% had liver tumors (10 of 23), 43% had proximal bile duct tumors (9 of 21), 15% had periampullary tumors (17 of 111), and 43% had pancreatic body and tail tumors (3 of 7). Nonoperative palliation was successful in all patients. However, late laparotomies were necessary in 7 of these 47 patients (15%); 5 patients with periampullary tumors and 2 patients with proximal bile duct tumors. All 7 patients underwent a surgical bypass, most due to duodenal obstruction, 1 to 13 months after diagnostic laparoscopy.

Conclusions: In this study, diagnostic laparoscopy may have prevented unnecessary laparotomies for exploration or palliation in 18% of all patients (40 of 226). The procedure is of doubtful benefit for patients with esophageal tumors because the current findings show that only 6% of explorative laparotomies could be prevented. In patients with periampullary tumors, the initial benefit was 15%, but the risk of a late laparotomy is relatively high (30%).

Background: Carcinoid tumors are unusual and most reports are anecdotal or limited in number. A series of 2837 cases was published in 1975. No receent large series is available.

Methods: The authors evaluated 5468 cases identified by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute (NCI) from 1973 to 1991 together with 2837 carcinoid cases previously registered by 2 earlier NCI programs. To the authors’ knowledge, the 8305 carcinoid tumors analyzed represent the largest current epidemiology series to date.

Results: The most frequent sites for carcinoid were the gastrointestinal (GI) tract (73.7%) and the bronchopulmonary system (25.1%). Within the GI tract, most occurred in the small bowel (28.7%), appendix (18.9%), and rectum (12.6%). For all sites, age-adjusted incidence rates were highest in African American males (2.12 per 100,000 population per year). Associated noncarcinoid tumors were frequent in conjunction with small intestinal (16.6%), appendiceal (14.6%), and colonic carcinoids (13.1%). The highest percentage of nonlocalized lesions were noted for pancreatic (76.1%), colonic (71.2%), and small intestinal carcinoids (70.7%) and this corresponded to their poor 5-year survival rates (34.1%, 41.6%, and 55.4%, respectively). The best 5-year survival rates were recorded for appendiceal (85.9%), bronchopulmonary (76.6%), and rectal carcinoids (72.2%). These exhibited invasive growth or metastatic spread in only 35.4%, 27.2%, and 14.2% of cases, respectively.

Conclusions: Carcinoids appear to have increased in incidence in the past 20 years. In part, this may be due to different surgical rules of the various registries, improved diagnostic technology, and increased awareness. A cumulative analysis of all types of carcinoid tumors in the SEER group indicates that in 45.3% metastases are already evident at the time of diagnosis. The overall 5-year survival rate of all carcinoid tumors regardless of site was 50.4% ± 6.4%.

Adjuvant chemotherapy (5-fluorouracil and levamisole) in Dukes’ B and C colorectal carcinoma. A cost-effectiveness analysis
J. Norum¹, B. Vonen², J.A. Olsen³, A. Revhaug^2
1Department of Oncology;
²Department of Surgery;
³Department of Economics, University of Tromso, Tromso, Norway.

Background: Adjuvant chemotherapy (5-fluorouracil, levamisole) is now standard practice in the treatment of Dukes’ B and C colorectal carcinoma (CRC), and this has increased the financial burden on health care systems world-wide.

Patients and Methods: Between 1993 and 1996, 95 patients in northern Norway were included in a national randomised CRC study, and assigned to surgery plus adjuvant chemotherapy or surgery alone. In April 1996, 94 of the patients were evaluable and 82 were still alive. The total treatment costs (hospital stay, surgery, chemotherapy, administrative and travelling costs) were calculated. A questionnaire was mailed to all survivors for assessment of the quality of their lives (QoL) (EuroQol questionnaire, a simple QoL-Scale, global QoL-measure of the EORTC QLQ-C30), and 62 of them (76%) responded.

Results: Adjuvant chemotherapy in Dukes’ B and C CRC raised the total treatment costs by £3,360. The median QoL was 0.83 (0-1 scale) in both arms. Employing a 5% discount rate and an improved survival of adjuvant therapy ranging from 5% to 15%, we calculated the cost of one gained quality-adjusted life-year (QALY) to be between £4,800 and £16,800.

Conclusion: Using a cut-off point level of £20,000 per QALY, adjuvant chemotherapy in CRC appears to be cost-effective only when the improvement in 5-year survival is ³ 5%. Adjuvant chemotherapy does not affect short-term QoL.

Infusional 5-fluorouracil in the treatment of gastrointestinal cancers: the Royal Marsden Hospital experience
P.J. Ross, A. Webb, D. Cunningham, J. Prendiville, A.R. Norman, J. Oates
Department of Medicine and the Gastrointestinal Unit, the Royal Marsden Hospital, London and Surrey, UK

Keywords: ambulatory chemotherapy; 5-fluorouracil; protracted venous infusion

Gastrointestinal malignancies remain among the most common causes of cancer death world-wide and surgical resection is the only therapeutic modality capable of cure. 5-Fluorouracil (5-FU) is the most active single agent in gastric and colorectal cancers with response rates of approximately 30% and 20%, respectively. Interest in infusional chemotherapy increased following a randomized trial in advanced colorectal cancer comparing bolus to infusional 5-FU demonstrated higher response rates with less toxicity in patients treated with infusional 5-FU. The Royal Marsden Hospital gastrointestinal unit has developed an ambulatory chemotherapy service. The studies have demonstrated that protracted venous infusion (PVI 5-FU) has high activity with low toxicity. In gastric cancer, the combination with epirubicin and cisplatin, the ECF regimen, has demonstrated a higher response rate and survival advantage compared to 5-FU, methotrexate and adriamycin. ECF has demonstrated a 40% response rate with one-year survival of 42% in hepatobiliary cancer whilst CF is effective in pancreatic cancer. In colorectal cancer PVI 5-FU achieved a response rate of 28% with one-year survival of 45%. The toxicity of PVI 5-FU is significantly less than the toxicity of folinic acid modulated bolus 5-FU. Tunnelled central venous catheters have been inserted in 832 patients with only 18% of catheters requiring removal for complications and minimal impacts on quality of life. Hospital-based cost analyses have demonstrated that ambulatory chemotherapy is cost-effective.

The cytotoxic activity of antimetabolite agents such as 5-fluorouracil (5-FU) is during the S phase of the cell cycle. However, 5-FU has a short plasma half life, approximately 11 minutes, and uptake of 5-FU is seen in only 3% of human colon cancer cells. Thus, only a small proportion of tumour cells are susceptible to each bolus dose. 5-FU acts via a cytotoxic metabolite fluorodeoxyuridine monophosphate (FdUMP) which binds to thymidylate synthase (TS). Folinic acid stabilises the complex formed between FdUMP and TS prolonging the duration of binding and increasing efficacy. However, FA-modulated 5-FU regimens may results in serious toxicity and toxic deaths have been observed. Infusional regimens increase the number of cells exposed to 5-FU whilst in the S phase of the cell cycle and are an alternative strategy for enhancing the efficacy of 5-FU. In metastatic colorectal cancer PVI 5-FU resulted in higher response rates than un modulated bolus 5-FU regimens with less toxicity, although survival was not improved. Short infusion (1-2 days) and PVI 5-FU have been demonstrated to ameliorate the toxicity of FA-modulated 5-FU. The higher response rates and improved toxicity profile of PVI 5-FU was the rationale for the Royal Marsden Hospital gastrointestinal unit studies in oesophagogastric, hepatobiliary, pancreatic and colorectal cancers.

Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials
R.G. Simonetti¹, A. Liberati², C. Angiolini², L. Pagliaro^3
1Divisione di Medicina. Ospedale V. Cervello, Palermo;
²Laboratorio di Epidemiologia Clinica, Istituto M. Negri Milan;
³Istituto di Medicina Generale e Pneumologia, Università di Palermo, Italy

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Many treatments have been proposed but considerable uncertainty still remains about their effectiveness. In this review we evaluated the quality, clinical coherence, consistency and results of Randomized Controlled Trials (RCT) of non-surgical treatments for HCC.

Methods: Thirty-seven RCTs examining the effect of different treatments were retrieved using MEDLINE (November 1978 to December 1995) and a review of reference lists. Selected aspects of the quality of design, conduct and reporting were examined. The odds ratio for the probability of surviving up to one year was calculated according to the Mantel-Haenszel-Peto method and displayed using l’Abbé plots.

Results: The 37 RCTs overall included 2803 patients (median 56, range 20-289). Patients prognosis varied widely across studies which also failed to report on important information about their characteristics. Only 10 RCTs had an untreated control group; the remaining 27 compared different regimens of intravenous or intraarterial chemotherapy with or without embolization of hepatic artery, hormono- and immunotherapy regimens. Some evidence of a moderate benefit emerged only from RCTs using tamoxifen and transcatheter arterial embolization vs. no treatment in unresectable patients: pooled odds ratio for 1-year survival were, respectively, 2.0 (95% confidence intervals (CI) 1.1-3.6) and 2.0 (95% CI 1.1-3.6). At 2 years, however, pooled odds ratio were no longer statistically significant for tamoxifen 1.2 (95% CI 0.6-2.6) but was significant for embolization 2.3 (95% CI 1.2-4.6). No evidence of efficacy was detected for embolization as adjuvant therapy in resected or transplantated patients nor for chemotherapy added to intra-arterial embolization.

Conclusions: This systematic review of RCTs on HCC, mostly in non resectable patients, indicate that the non-surgical current treatments are ineffective or minimally and uncertainly, effecttive. The three treatment modalities minimally and uncertainly effective (i.e., embolization, tamoxifen and IFN) can deserve further assessment by larger and methodologically more sound randomized trials.

Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer
B. Glimelius¹, K. Ekström¹, K. Hoffman^1-3, W. Graf². P-O Sjödén, U. Haglund², C. Svensson⁴, L.-K. Enander⁵, T. Linné⁶, H. Sellström⁷, R. Heuman^8
1Department of Oncology; and ²Surgery, and ³Centre for Caring Sciences, University of Uppsala, Uppsala;
⁴Department of Oncology, Huddinge University Hospital, Stockholm; Department of ⁵Surgery and ⁶Oncology, Centralsjukhuset, Karlstad;
⁷Department of Surgery; Sjukhuset, Säffle;
⁸Department of Surgery; Lasarettet, Mora, Sweden

Background: The extent to which chmeotherapy may relieve tumour-related symptoms, improve quality of life and prolong survival in patients with gastric cancer is not known in spite of the extensive use of this treatment modality. The aim of this study was to estimate any gain in the quantity and quality of life produced by chemotherapy in these patients.

Patients and methods: Between January 1991 and February 1995, 61 patients with gastric cancer were randomized to either chemotherapy in addition to best supportive care or to best supportive care. Chemotherapy was allowed in the latter group if the supportive measures did not lead to palliation. Chemotherapy was the ELF - regimen consisting of 5-fluorouracil, leucovorin and etoposide, or, in elderly patients with poor performance, a 5-fluorouracil/leucovorin regimen (FLv). Quality of life was evaluated with the EORTC-QLQ-C30 instrument.

Results: More patients in the chemotherapy group (45%, 14/31) had an improved or prolonged high quality of life for a minimum period of 4 months compared to those in the best supportive care group (20%, 6/30, P < 0.05). A similar difference was seen in the treating physician’s evaluation of whether the patient was subjectively improved or continued to do well for at least 4 months (17/31, 55% versus 6/30, 20%, P < 0.01). Overall survival was longer in the chemotherapy group (median 8 vs. 5 month) although the difference was not statistically significant (P = 0.12). After corrections for imbalances in pretreatment characteristics, chemotherapy treatment was, however, associated with a survival benefit (P = 0.003). Also, the quality-adjusted survival time and time to disease progression were longer for patients randomized to chemotherapy (median 5 vs. 2 months, P = 0.03).

Conclusions: The results show that chemotherapy can add to both quantity and quality of life in advanced gastric cancer. The number of patients who benefit from treatment is, however, still rather limited.

Randomised study of screening for colorectal cancer with faecal-occult-blood test
Ole Kronborg, Claus Fenger, Jørn Olsen, Ole Dan Jørgensen, Ole Søndergaard

Background: Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood (FOB) tests can lead to a reduction in mortality from colorectal cancer (CRC). The aim of this randomised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls.

Methods: 140 000 people aged 45-75 years lived in Funen, Denmark, in August, 1985, and were considered for inclusion in our study. Before randomisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study. Randomisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group (30,967), three per 14 to the control group (30,966), and eight not be enrolled in the study (75,552). Controls were not told about the study and continued to use health-care facilities as normal. Hemoccult-II blood tests (with dietary restrictons but without rehydration) were sent to screening-group participants. Only those participants who completed the first screening round were invited for further screening - five rounds of screening during a 10-year period. Participants with positive tests were asked to attend a full examination and were offered colonoscopy whenever possible. The primary endpoint was death from CRC.

Findings: Of the 30,967 screening-group participants, 20,672 (67%) completed the first screening round and were invited for further screening; more than 90% accepted repeated screenings. During the 10-year study, 481 people in the screening group had a diagnosis of CRC, compared with 483 unscreened controls. There were 205 deaths attributable to CRC in the screening group, compared with 249 deaths in controls. CRC mortality, including deaths attributable to complications from CRC treatment, was significantly lower in the screening group than in controls (mortality ratio 0.82 [95% CI 0.68-0.99]) p = 0.03).

Interpretation: Our findings indicate that biennal screening by FOB tests can reduce CRC mortality. This study is being continued to improved its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence

Randomised controlled trial of faecal-occult-blood screening for colorectal cancer
Jack D. Hardcastle, Jocelyn O. Chamberlain, Michael H.E. Robinson, Susan M. Moss, Satya S. Amar, Tom W. Balfour, Peter D. James, Christine M. Mangham

Background: There is growing evidence that faecal-occult-blood (FOB) screening may reduce colorectal cancer (CRC) mortality, but this reduction in CRC mortality has not been shown in an unselected population-based randomised controlled trial. The aim of this study was to assess the effect of FOB screening on CRC mortality in such a setting.

Methods: Between February, 1981, and January, 1991, 152,850 people aged 45-74 years who lived in the Nottingham area of the UK were recruited to our study. Participants were randomly allocated FOB screening (76,466) or no screening (controls: 76,384). Controls were not told about the study and received no intervention. Screening-group participants were sent a Haemoccult FOB test kit with instructions from their family doctor. FOB tests were not rehydrated and dietary restrictions were imposed only for retesting borderline results. Individuals with negative FOB tests at the first screening, together with those who tested positive but in whom no neoplasia was found on colonoscopy, were invited to take part in further screening every 2 years. Screening was stopped in February, 1995, by which time screening-group participants had been offered FOB tests between three and six times. Screening-group participants who had a positive test were offered full colonoscopy. All participants were followed up until June, 1995. The primary outcome measure was CRC mortality.

Findings: Of the 152,850 individuals recruited to the study, 2,599 could not be traced or had emigrated and were excluded from the analysis. Thus, there were 75,253 participants in the screening group and 74,998 controls. 44,838 (59.6%) screening-group participants completed at least one screening. 28,720 (38.2%) of these individuals completed all the FOB tests they were offered and 16,118 (21.4%) completed at least one screening but not all the tests they were offered. 30,415 (40.4%) did not complete any test. Of 893 cancers (20% stage A) diagnosed in screening-group participants (CRC incidence of 1.49 per 1,000 person-years), 236 (26.4%) were detected by FOB screening, 249 (27.9%) presented after a negative FOB test or investigation, and 400 (44.8%) presented in non-responders. The incidence of cancer in the control group (856 cases, 11% stage A) was 1.44 per 1,000 person-years. Median follow-up was 7-8 years (range 4.5-14.5), 360 people died from CRC in the screening group compared with 420 in the control group - a 15% reduction in cumulative CRC mortality in the screening group (odds ratio = 0.85 [95% CI 0.74-0.98], p = 0.026).

Interpretation: Our findings together with evidence from other trials suggest that consideration should be given to a national programme of FOB screening to reduce CRC mortality in the general population.

Tobacco, colorectal cancer, and adenomas: a review of the evidence
Edward Giovannucci, Maria Elena Martínez

Although tobacco has been clearly implicated as a cause of a number of cancers, earlier studies had not generally found cigarrette smokers to be at higher risk for cancers of the large bowel. Unlike the earlier studies, more recent studies have tended to find cigarette smokers to be at higher risk of colorectal cancer. In addition, cigarette smoking has been consistently associated with a higher risk of colorectal adenomas, percursors of cancers. We hypothesize that smoking is an initiator of colorectal carcinogenesis. The consistent finding of a positive association between smoking and risk of adenomas may reflect the presumably shorter induction period for these lesions. Recent studies indicate that an increased risk for large-bowel cancer emerges only after about four decades after one begins smoking, perhaps accounting for the null studies that were conducted earlier during the smoking epidemic. Most studies had not taken into account an induction period between timing of smoking and risk for cancer. The increasing male-to-female mortality ratio from colorectal cancer over the latter half of this century in the United States may have been a result of tobacco use by men earlier in the century. If the associations observed with colorectal adenomas and cancers in recent studies are causal, approximately 20% of the large-bowel cancers in men would be attributable to smoking. On the basis of the strength of the available evidence, intensified effort to prevent smoking among young people is warranted.

Calcium, vitamin D, and the occurrence of colorectal cancer among women
María Elena Martínez, Edward L. Giovannucci, Graham A. Colditz, Meir J. Stampfer, David J. Hunter, Frank E. Speizer, Alvin Wing, Walter C. Willett

Background: Despite evidence from animal studies for a protective effect of higher calcium and possibly vitamin D intake against colorectal cancer, epidemiology studies have been inconclusive.

Purpose: We investigated the associations between the intake of calcium and vitamin D and the occurrence of colorectal cancer.

Methods: In a prospective study, 89,448 female registered nurses who were free of cancer responded to a mailed, semiquantitative food-frequency questionnaire in 1980; dietary information was updated in 1984 and 1986. Through 1992, 501 incident cases of colorectal cancer (396 colon and 105 rectal cancers) were documented. As measures of exposure, we used nutrient intake in 1980 and also two measures of long-term intake on the basis of the three questionnaires: the average of intakes from the three questionnaires and consistent intakes, which were defined as high if women were in the upper tertile on all questionnaires and low if they were in the lower tertile on all questionnaires. To further characterize long-term intake, we conducted analyses excluding women who reported a change in their consumption of milk (primary source of calcium and vitamin D) in the 10 years prior to 1980. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the lowest quintile of intake as a reference. The Mantel extension test was used to evaluate linear trends across the categories of nutrient intake. In multivariate analyses, the trends were tested with use of the medians of the intake as a continuous variable in the logistic model. The P values for the trends were two-sided.

Results: On the basis of the data from the 1980 questionnaire alone, the multivariate RR for colorectal cancer for women in the upper versus the lower quintile were 0.80 (95% CI = 0.60-1.07) for dietary calcium, 0.84 (95% CI = 0.63-1.13) for dietary vitamin D (from foods only), and 0.88 (95% CI = 0.66-1.16) for total vitamin D (from foods and supplements). After the exclusion of women who reported a change in their milk intake, the RRs for colorectal cancer for the highest versus the lowest categories of average intake were 0.74 (95% CI = 0.36-1.50) for dietary calcium, 0.72 (95% CI = 0.34-1.54) for dietary vitamin D, and 0.42 (95% CI = 0.19-0.91) for total vitamin D. The corresponding RRs for the consistency analyses were 0.70 (95% CI = 0.35-1.39) for dietary calcium, 059 (95% CI = 0.30-1.16) for dietary vitamin D, and 0.33 (95% CI = 0.16-0.70) for total vitamin D.

Conclusions: These findings do not support a substantial inverse association between calcium intake and risk of colorectal cancer, but an inverse association between intake of total vitamin D and risk of colorectal cancer was suggested.

Implications: Available evidence does not warrant an increase in calcium intake to prevent colon cancer, but longer-term studies of both calcium and especially vitamin D in relation to colorectal cancer risk are needed.

Current controversies in cancer. Is intra-arterial chemotherapy worthwhile in the treatment of patients with unresectable hepatic colorectal cancer metastases?
A.M. Cohen¹, N.E. Kemeny², C.-H. Köhne, J. Wils, P.G. de Takats, D.J. Kerr
¹Department of Surgery and ²Gastroenterology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Cornell University Medical College, New York, New York 10021-6007, U.S.A.

The use of drugs with short half-lives, which are rapidly cleared from the bloodstream, have a pharmacokinetic advantage when given by regional infusion. Primary and secondary hepatic tumours greater than 3 mm in size obtain most of their blood supply from the hepatic artery, while the normal hepatocytes derive their blood supply mostly from the portal circulation. Chemotherapeutic drugs that would be most attractive for regional infusion are substantially extracted by the liver during the first pass, thus producing lower peripheral drug levels and systemic toxicity. These are the three major theoretical benefits for hepatic artery infusion (HAI) chemotherapy, as long as the appropriate chemotherapy drugs are utilised. For perspective, the regression rate for systemic chemotherapy with 5-fluorouracil/leucovorin (5-FU/LV), generally the standard regimen at this time, is 20-40%. One might argue that all patients with hepatic metastases eventually develop disseminated cancer. However, autopsy data reported by Weiss indicate that 46% of patients dying of colorectal cancer hepatic metastases have disease limited to their liver. In addition, disseminated disease is frequently a late phenomenon, with cancer death related to liver failure or associated inanition. As with surgical resection, a regional strategy may produce only a modest improvement in median survival, but a significant ‘tail on the curve’ with prolonged survival of a subset of patients.

Ensminger and colleagues measured drug levels from hepatic venous catheters, and demonstrated that the hepatic extraction of 5-fluorodeoxyuridase (FUdR) was 4-fold higher after hepatic arterial injection compared to systemic injection. The ability to administer a higher dose locally exposes tumours to a higher drug concentration than can be achieved with systemic therapy. Since most drugs have a steep dose-response curve, their antineoplastic efficacy should be increased by HAI.

Initial clinical trials of hepatic artery chemotherapy used percutaneous systems. The initial report of a study using an implantable pump and continuous FUdR therapy indicated an 83% response rate. Despite the fact that other investigators using this technique and drug could not reproduce such high responses, the mean response rate of 44% in 10 trials (where 42% of the patients were previously treated) was higher than the mean response rate obtained with systemic chemotherapy at that time.

Stereotactic radiosurgery for the treatment of brain metastases. Results of a single institution series
John C. Breneman, MD, Ronald E. Warnick, MD, Robert E. Albright Jr., MD, Noppakoon Kukiatinanit, MD, Jodi Shaw, RT, David Armin, John Tew Jr., MD

Background: Stereotactic radiosurgery is being used with increasing frequency for the treatment of brain metastases. Optimal patient selection and treatment factors continue to be defined. This study provides outcome data from a single institutional experience with radiosurgery and identifies parameters that may be useful for the proper selection and treatment of patients.

Methods: Eighty-four patients underwent stereotactic radiosurgery for brain metastases between September 1989 and November 1995. Seventy-nine patients (93%) were treated at recurrence after previous whole brain radiotherapy. Patients had between 1 and 6 lesions with a median minimum tumor dose of 1600 centigrays (cGy). Thirty-eight patients (45%) had active extracranial disease at the time of radiosurgery.

Results: Median survival for the entire group was 43 weeks from the date of radiosurgery and 71 weeks from the original diagnosis of brain metastases. Patients with 1 or 2 metastases had significantly improved survival compared with patients with ³ 3 metastases (P = 0.02), and patients without active extracranial tumor survived longer than those with extracranial disease (P = 0.03). Median time to failure for 145 evaluable lesions was 35 weeks. Local control was significantly improved for radiosurgery doses >: 1800 cGy, and for melanoma histology.

Conclusions: These results are comparable to reports of patients treated with resection and significantly superior to results observed after whole brain radiotherapy. The authors conclude that stereotactic radiosurgery is an effective, low risk treatment for extending the survival of patients with recurrent brain metastasis. Although survival is best for patients with £ two lesions and no active extracranial disease, selected patients with > two lesions or active extracranial tumor may benefit as well.

Malignant cerebral glioma - I: Survival, disability, and morbidity after radiotherapy
Elizabeth Davies, Charles Clarke, Anthony Hopkins

Objective: To describe survival, disability, and morbidity after radiotherapy for malignant glioma.

Design: Two year prospective study with home interviews with patients and relatives.

Settings: Seven neurosurgical and radiotherapy centres in London.

Subjects: 105 patients aged 21 to 75: 59 had biopsy; 46 had partial macroscopic resection; 92 received radiotherapy; and 13 received steroids alone.

Main outcome measures: Survival, time free from disability, and changes in disability after treatment.

Results: Six and 12 month survival for radiotherapy patients was 70% and 39%, respectively. Age, World Health Organisation clinical performance status, extent of surgery, and history of seizures before diagnoses each influenced survival. The Medical Research Council prognostic index was also significantly related to survival. Multivariate analysis showed that initial clinical performance status was the most important component of the index. Most (80%; 49/61) patients with a clinical performance status of 0, 1, or 2 lived at least six months before becoming permanently disabled. Most patients who had initially had a good clinical performance status (0-2) and who were alive six months after radiotherapy (68%; 36/52), however, had experienced either clinical deterioration or severe tiredness after treatment. In 17% (9/52) of these some permanent loss of function remained. These adverse effects were associated with increasing radiotherapy dose. Severely disabled patients (clinical performance status 3 or 4) gained little benefit.

Conclusion: Severely disabled patients gain little physical benefit from radiotherapy, whereas those not so disabled may experience considerable adverse effects.

Malignant cerebral glioma - II: Perspectives of patients and relatives on the value of radiotherapy
Elizabeth Davies, Charles Clarke, Anthony Hopkins

Objective: To explore the experiences of patients and relatives after the diagnosis and treatment of malignant cerebral glioma.

Design: Two year prospective study with home interviews.

Setting: Six neurosurgery and radiotherapy centres in London.

Subjects: 75 patients and 66 close relatives interviewed at diagnosis, 58 patients interviewed after radiotherapy, and 27 interviewed after recurrence.

Main outcome measures: Awareness of likely prognosis, distress, dissatisfaction with radiotherapy, and perception of severe problems in everyday life.

Results: As they began radiotherapy most patients understood that they suffered from a brain tumour (95%; 71/7), but only one quarter (19/75) seemed fully aware of the poor prognosis. Others were unaware (43%; 32/75) or only partly aware (32%; 24/75). The more aware patients were more distressed. Relatives were three times more likely to be aware of the prognosis (67%; 44/66) and were more distressed. Although 39% (29/75) of patients initially made negative comments about radiotherapy, only 17% (13/75) were completely dissatisfied. The decision to accept radiotherapy could be discussed directly with 19 fully aware patients. Twelve found radiotherapy acceptable if it were medically advised or if it improved survival. Assessed by their own reports of problems only 40% of patients achieved a period of stability or remission, yet dissatisfaction with treatment did not increase.

Conclusion: Most patients with malignant glioma initially seemed unaware or only partly aware of the poor prognosis. Relatives were more aware, more distressed, and often concerned to protect patients from full awareness, which made it difficult to explore with patients directly the possible trade off between quality and length of life. Conceptualising the question as a rational choice ignores the social and emotional context of life threatening disease.

p53-independent apoptosis: a mechanism of radiation-induced cell death of glioblastoma cells
Daphne A. Haas-Kogan, MD, Paul Dazin, MD, Lily Hu, MD, Dennis F. Deen, MD, Mark A. Israel, MD, San Francisco, California

Purpose: Radiation therapy, though routinely used in the treatment of patients with glioblastoma multiforme, is of limited efficacy in extending patients’ lives. In this study we investigated the mechanism by which ionizing radiation causes death of glioblastoma cells in the hope of ultimately altering the intrinsic radioresistance of glioblastoma tumors.

Methods: Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Radiation-induced apoptosis was assayed by fluorescence-activated cell sorter analysis, terminal deoxynucleotide transferase labeling technique, and chromatin morphology. Cellular distribution within the cell cycle was quantitated by dual labeling with propidium iodide and bromodeoxyuridine.

Results: We examined whether in vitro clonogenic radioresistance of glioblastoma would reflect their susceptibility to radiation-induced apoptosis and their ability to undergo a G1 arrest- two cellular functions associated with wild-type p53 expression. We demonstrated that apoptosis contributed to the cytocidal effect of ionizing radiation on glioblastoma cells. The apoptosis observed in glioblastoma cell lines occurred in the absence of wild-type p53 expression. We identified a glioblastoma cell line expressing wild-type p53 and found that it did not exhibit radiation-induced apoptosis but rather underwent a prolonged G1 arrest not observed in any glioblastoma cell line lacking wild-type p53 expression.

Conclusion: Apoptosis is an important component of the lethal effect of ionizing radiation on glioblastomas cells and does not require wild-type p53 expression. Glioblastoma expressing wild-type p53 exhibited no apoptosis, even after high radiation doses, but rather underwent a prolonged G1 arrest. The observation of p53-independent apoptosis and p53-dependent G1 arrest in glioblastoma cells have important radiobiologic and clinical implications.

Factores estadísticamente significativos en la supervivencia de los pacientes con cáncer de esófago
A. González Navarro, A. García Pérez, A. Ruiz Díez, M.J. González Hernández

Propósito: El objetivo del trabajo es analizar algunas de las covariables más importantes que definen el Cáncer de Esófago y que son recogidas en los registros hospitalarios de tumores y ver cuáles son estadísticamente significativas a la hora de determinar la supervivencia en los pacientes afectados por esta enfermedad.

Material y Métodos: En total se han incluido 66 tumores del Esófago con los que se han realizado los siguientes estudios: un análisis estadístico de tipo descriptivo y un análisis de supervivencia mediante un modelo log-lineal paramétrico que se ha resuelto con un modelo de Tiempo de Fallo Acelerado por el cual se infiere cuál de las covariables consideradas (Hospital en el que se registró el tumor, Histología, Tratamiento, Localización Tumoral, Extensión Tumoral, Tumores Primarios Múltiples y Edad), son significativas a la hora de explicar el tiempo de supervivencia de los pacientes.

Resultados: Con este análisis resultan estadísticamente significativas la Histología, el Tratamiento, la Extensión y la existencia de tumores Primarios Múltiples. No resultando significativas la Localización Tumoral, el Hospital ni la Edad.

Conclusioes: A la luz del estudio realizado podemos afirmar que la supervivencia de los tumores registrados en el SIDC está relacionada significativamente con las variables Histología, tipo de Tratamiento, Extensión y la presencia o no de Tumores Primarios Múltiples. La variables Localización tumoral, Hospital donde se es tratado y Edad, no parecen intervenir. Este tipo de estudios que los registros de Tumores Hospitalarios permiten, abren líneas de trabajo con una mayor profundidad y deben ser realizadas en el ánimo de una cooperación entre diversas instituciones.