 Vol.44 n° 1
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Prognosis among African-American women and white women with lympnode negative breast
carcinoma
1 Department of Biostatistics and National Surgical Adjuvant Breast and Bowel Project,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania;
Background. A disparity in breast carcinoma survival between African-American and white women has been noted over the past several decades. A major factor implicated in this disparity is stage of disease at diagnosis. In this study, survival and related endopoints were examinated among African-American women and white women with lymph node negative breast carcinoma who participated in two randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP).
Methods. Patients from two studies, one conducted among patients with estrogen receptor (ER) negative tumors and the other among patients with ER positive tumors, were included. Study goals were to determine whether African-Americans and whites had comparable outcomes, accounting for ER status and differences in patient characteristics at diagnosis, and to determine whether treatment response was similar for African-Americans and whites.
Results. Five-year survival rates were 83% for African-Americans and 85% for whites among ER negative patients, and 93% for African-Americans and 92% for whites among ER positive patients. Rates of disease free survival (DFS) (i.e., time to disease recurrence, second primary cancer, or death) were 71% for African-Americans and 74% for whites at 5 years among ER negative patients, and 81% for African-Americans and 80% for whites among ER positive patients. African-Americans tended to have less favorable baseline prognostic characteristics. Adjusted relative risk (RR) estimates indicated similar prognosis for African-Americans compared with whites for mortality (African-American/white RR = 1.02 with 95% confidence interval [C], 0.66-1.56 among ER negative patients; RR = 1.14 with 95% CI, 0.84-1.54 among ER positive patients) and DFS (RR = 0.98 with 95% CI, 0.70-1,37 for ER negative patients; RR = 0.96 with 95% CI, 0.75-1.22 for ER positive patients). Estimated percent reductions in DFS events for patients receiving adjuvant therapy were 32% for ER negative African-Americans, 36% for ER negative whites, 20% for ER positive African-Americans, and 39% for ER positive whites.
Conclusions. African-American and white patients with localized breast carcinoma had similar outcomes and benefited equally from systemic therapy. These results suggest that early detection and appropriate therapy among African-American patients could result in a reduction in the current disparity in breast carcinoma mortality between African-Americans and whites.
Pelvic computed tomography of breast carcinoma patients
Should it routinely be added to abdominal computed tomography?
1 Department of Diagnostic Radiology, Cleveland Clinic Foundation, Cleveland, Ohio;
Background. This study was conducted to determine if pelvic computed tomography (CT) should routinely be appended to abdominal CT in the workup of patients with breast carcinoma.
Methods. The abdominal-pelvic CTs of 139 breast carcinoma patients (195 exams) were reviewed. Scans were grouped by indication and whether pelvic pathology was know before CT. Pelvic CT results were correlated with their effect on patient management.
Results. Among the 119 patients without pre-CT evidence of pelvic disease, a nonosseous pelvic metastasis was identified in only 1; this patient also had liver metastases and management was not changed. No unsuspected pelvic CT finding altered therapy for breast carcinoma. However, three patients underwent surgery for asymptomatic masses discovered on pelvic CT; all were benign.
Conclusions. Pelvic CT is unlikely to affect the management of patients with breast carcinoma by detecting occult metastatic disease.
Induced abortation and the risk of breast cancer
Background: It has been hypothesized that an interrupted pregnancy might increase a woman’s risk of breast cancer because breast cells could proliferate without the later protective effect of differentiation.
Methods: We established a population-based cohort with information on parity and vital status consisting of all Danish women born from April 1, 1935, through March 31, 1978. Through linkage with the National Registry of Induced Abortions, information on the number and dates of induced abortions among those women was combined with information on the gestational age of each aborted fetus. All new cases of breast cancer were identified through linkage with the Danish Cancer Registry.
Result: In the cohort of 1.5 million women (28.5 million person-years), we identified 370,715 induced abortions among 280,965 women (2.7 million person-years) and 10,246 women with breast cancer. After adjustment for known risk factors, induced abortion was not associated with an increased risk of breast cancer (relative risk, 1.00; 95 percent confidence interval, 0.94 to 1.06). No increases in risk were found in subgroups defined according to age at abortion, parity, time since abortion, or age at diagnosis of breast cancer. The relative risk of breast cancer increased with increasing gestational age of the fetus at the time of the most recent induced abortion: < 7 weeks, 0.81 (95 percent confidence interval, 0.58 to 1.13); > 12 weeks, 1.38 (1.00 to 1.90) (reference category, 9 to 10 weeks).
Conclusions: Induced abortions have no overall effect on the risk of breast cancer.
Postmenopausal hormone therapy and mortality
Background. Postmenopausal hormone therapy has both benefits and hazards, including decreased risks of osteoporosis and cardiovascular disease and an increased risk of breast cancer.
Methods. We examined the relation between the use of postmenopausal hormones and mortality among participants in the Nurse’s Health Study, who were 30 to 55 years of age at base line in 1976. Data were collected by biennial questionnaires beginning in 1976 and continuing through 1992. We documented 3637 deaths from 1976 to 1994. Each participant who died was matched with 10 controls alive at the time of her death. For each death, we defined the subject’s hormone status according to the last biennial questionnaire before her death or before the diagnosis of the fatal disease; this reduced bias caused by the discontinuation of hormone use between the time of diagnosis of a potentially fatal disease and death.
Results. After adjustment for confounding variables, current hormone users had a lower risk of death (relative risk, 0.63; 95 percent confidence interval, 0.56 to 0.70) than subjects who had never taken hormones; however, the apparent benefit decreased with long-term use (relative risk, 0.80; 0.67 to 0.96, after 10 or more years) because of an increase in mortality from breast cancer among long-term hormone users. Current hormone users with coronary risk factors (69 percent of the women) had the largest reduction in mortality (relative risk, 0.51; 95 percent confidence interval, 0.45 to 0.57), with substantially less benefit for those at low risk (13 percent of the women; relative risk, 0.89; 95 percent confidence interval, 0.62 to 1.28).
Conclusions. On average, mortality among women who use postmenopausal hormones is lower than among nonusers; however, the survival benefit diminishes with longer duration of use and is lower for women at low risk for coronary disease.
Locally advanced breast cancer: early results of a randomised trial of multimodal therapy versus initial hormone therapy
1 Professorial Department of Surgery, City Hospital, Nottingham; and
The aim of this study was to investigate initial treatment of locally advanced breast cancer. Patients were randomised to “multimodal” therapy (pre-operative chemotherapy, Patey mastectomy, flap irradiation and adjuvant hormone therapy) (n = 55), or initial “hormone” therapy (n = 53) with further therapy upon tumor progression. The objective response to chemotherapy was 57% (31/54) after four cycles. Of patients on hormone therapy, 36% (19/55) had an objective response and 32% (17/33) disease stasis at a 6 month assessment. At a median 30 months follow-up, there was no notable difference in development of metastases or survival: only 6 patients have uncontrolled loco-regional relapse (4 “hormonal”, 2 “multimodal”). The number of treatments per patient required for this loco-regional control was lower in the “hormone” group (mean 2.13 versus 4.20 in the “multimodal” group). This small study has shown that the use of consecutive therapies, with the aim of tumour control, does not appear to compromise outcome in comparison with initial “multimodal” therapy. Adopting such a policy may allow some patients to avoid unnecessary treatments.
Increasing incidence of and declining mortality from breast carcinoma
Trends in Malmö, Sweden, 1961-1992
1 Department of Surgery, Malmö University Hospital, Malmö, Sweden;
Background. The incidence of breast carcinoma is increasing in most populations, whereas mortality caused by this disease is fairly constant. The authors analyzed the incidence of and mortality from invasive breast carcinoma in a population with access to good medical care, into which mammographic screening was introduced in 1976 and adjuvant therapy in 1978.
Methods. In a consecutive series of patients with invasive breast carcinoma from Malmö, 1961-1991, changes in age-adjusted incidence were analyzed and compared with incidence of the disease in the rest of Sweden. Age-adjusted breast carcinoma mortality was studied for the period 1964-1992.
Results. The introduction of mammographic screening was associated with an increase in breast carcinoma incidence. This was restricted to the age group that was eligible for screening (age 45-69 years) and to Stage I disease. Between 1977 and 1992, age-adjusted breast carcinoma mortality decreased in Malmö by 43% (95% CI, 26-56%) as compared with 12% (95% CI, 8-16%) in the rest of Sweden. The decrease was statistically significant in both populations and significantly greater in Malmö than in the rest of Sweden (P < 0.001). In Malmö the decrease was seen in two age groups, age 45-69 years and age 70 years and older. In the rest of Sweden the decrease was seen only among women age 70 years and older. There were no changes in incidence or mortality among women younger than 45 years in either population.
Conclusions. Breast carcinoma incidence was strongly related to diagnostic activity, especially mammographic screening. The decrease in mortality occurred in temporal relation to the introduction of screening and adjuvant therapy, making a caudal relation likely. The difference in results between Malmö and the rest of Sweden indicates an important role for screening in mortality reduction. [See editorial on pages 1-2, this issue.]
Mammography screening interval and the frequency of interval cancers in a population-
based screening
1 Turku University Central Hospital, FIN-20520 Turku. Finland;
Summary.: In a population-based mammography screening, 129,731 examinations were carried out among 36,000 women aged 40-74 in the city of Turku. Finland, in the period 1987-94. Women older than 50 were screened at 2-year intervals, and those younger than 50 at either 1-year or 3-year intervals, depending on their year of birth. Screen-detected breast cancers numbered 385 and, during the same time period, 154 women were diagnosed with breast cancer outside screening in the same age group in the same city, and 100 interval cancers were detected. Two hundred and fifty (67%) of the screen-detected cancers were of post-surgical stage I compared with 45 (45%) of the interval cancers and 52 (34%) of the cancers found outside screening (P < 0.0001). However, among women aged 40-49 the frequency of stage I cancers did not differ significantly among screen-detected cancers, interval cancers and cancers found outside screening (50%, 42% and 44% respectively; P = 0.73). Invasive interval cancers were more frequently among women aged 40-49 if screening was done at either 1-year (27%) or 3-year intervals (39%) than in older women screened at 2-year intervals (18%; P = 0.08 and P = 0.0009 respectively). Even if adjusted difference in the S-phase fraction size was found between cancers of women younger than 50 and those older than this (P = 0.13). We conclude that more interval cancers were found among women younger than 50 than among those older than 50 and that this could not be explained by the rate of cancer cell proliferation
The national cancer data base report on the results of a large nonrandomized comparison of breast preservation and modified radical mastectomy
1 Department of Surgery, Northwestern University Medical School, Chicago, Illinois;
Data in this report were collected by the National Cancer Data Base, a joint project of the Commission on Cancer of the American College of Surgeons, and the American Cancer Society.
Address for reprints: Herman R. Menck, M.B.A., American College of Surgeons Commission on Cancer, Manager of Clinical Information, 55 East Erie Street, Chicago, IL 60611-2797.
Received November 18, 1996; revision received February 13, 1997; accepted March 14, 1997.
Background. Although the conclusions reached in the National Surgical Adjuvant Bowel and Breast Protocol ß-06 trial and other clinical trials appear to remain intact, questions persist regarding the equivalency of breast preservation compared with modified radical mastectomy for patients with invasive carcinoma. Documentation and assessment of comparative survival rates in a large cohort of nonrandomized breast carcinoma patients was undertaken to understand better these outcome patterns.
Methods. Information gathered from the medical records of 96,030 women diagnosed with early stage carcinoma of the breast between 1985 and 1988 was reviewed to determine the age at diagnosis; tumor stage, grade, dimension; treatment; and disease status.
Results. Of these 96.030 Stage I and II (based on the American Joint Committee on Cancer staging system) patients, 8583 (8.9%) were treated with segmental mastectomy, axillary lymph node dissection, and radiotherapy without systemic treatment. Three thousand seven hundred and ninety-seven patients (4.0%) were treated with segmental mastectomy, axillary lymph node dissection, radiotherapy, and systemic therapy. Forty-four thousand two hundred and forth-nine patients (46.0%) were treated with modified radical mastectomy without systemic therapy, and 18,322 patients (19.1%) were treated with modified radical mastectomy with systemic therapy. Within each stage, reported survival was equal to or more favorable for patients managed with breast preservation compared with those treated with modified radical mastectomy. This comparability was observed in all subsets analyzed including those defined by age at diagnosis, histologic grade, and tumor dimension.
Conclusions. These findings are consistent with the hypothesis that AJCC Stage I and II patients treated with breast preservation appear to have survival rates equivalent to those treated with modified radical masctectomy.
Estrogen replacement therapy for the breast cancer survivor: a reappraisal
Introduction
Given the millions of American women who have survived this disease, which has an annual incidence in the United States of 180-185,000 cases and an overall disease-free survival at 5 years in excess of 70%, there is ample reason for study of this controversial question. In addition, the recent broadening of indications for adjuvant chemotherapy has created greatly increased numbers of premenopausal patients (ages 25-45) who are rendered prematurely menopausal by the effect of the cytotoxic drugs on their ovarian function.
In the last two decades, two demographic trends have heightened awareness concerning menopause and its health consequences. First and foremost, women are living longer. Life expectancy for U.S. women in 1900 was age 45, and now it is close to 80. Most women are spending fully 40% of their life after menopause. Second, more women than ever will enter the menopausal years in the next decade as millions of babyboomers, those born after World War II, enter their fifties. The proportion of all U.S. women older than 45 years of age will grow from 34% in 1995 to 43% in the year 2020.
Childbearing issues in breast carcinoma survivors
Background. The issue of the subsequent pregnancy after breast carcinoma treatment is of paramount importance to young survivors and their oncologists. Matters related to having children, whether biologic or not, are analyzed.
Methods. Available evidence on the role of estrogen in the carcinogenesis and promotion of breast carcinoma is summarized. The scanty literature on pregnancy in breast carcinoma survivors is reviewed and evaluated. With reference to infertility as the result of adjuvant treatment, studies on therapy-induced amenorrhea are cited.
Results. The survival of women with breast carcinoma is not decreased by subsequent pregnancy in any of the published series. Nevertheless, several biases may be present, making the results less than conclusive; no prospective studies exist. Theoretic concern of tumor promotion may be justified when considering the long term exposure to intense gestational hormones in the presence of established breast carcinoma with possible micrometastases. As a separate issue, the common situation of chemotherapy-induced amenorrhea may not permit pregnancy. Information for the breast carcinoma survivor on assisted conception and adoption is limited.
Conclusions. Further research on the safety of subsequent pregnancy after breast carcinoma treatment is needed; the authors report that they are initiating a multicenter prospective study to address these issues.
Importance of findings on the initial evaluation for
cancer in patients with symptomatic idiopathic deep venous thrombosis
1 Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer
Center, Houston, Texas;
Background. Pretreatment serum prostate specific antigen (PSA) level is a powerful prognostic factor for clinically localized prostate carcinoma. The traditional prognostic factors, T classification and Gleason score, appear to have been relegated to a minor position. This study was conducted to evaluate the relative prognostic roles of PSA, T classification, and Gleason score in a large cohort of men irradiated in the PSA era.
Methods. The authors analyzed the outcome for a group of 938 men with T1-T4, N0 or NX, M0 prostate carcinoma who received definitive external beam radiation therapy as their only initial treatment during the period 1987-1995. The T classification were as follows: T1, 283 (30%); T2, 360 (38%); T3/T4, 295 (31%). Gleason scores were as follows: Gleason 2-6, 580 (62%); Gleason 7, 224 (24%); Gleason 8-10, 122 (13%). Pretreatment PSA levels (ng/mL) were as follows: PSA £ 4, 167 (18%); PSA 4 to £ 10, 363 (39%); PSA 10 to £ 20, 259 (28%); PSA > 20, 149 (16%). At a mean follow-up of 43 months (range, 6-106 months), disease outcome specified as relapse/rising PSA, local recurrence, or metastasis was analyzed using univariate and multivariate techniques.
Results. The 6-year actuarial incidences of relapse/rising PSA, local recurrence, and metastases were 48%, 27%, and, 6%, respectively. In multivariate regression, pretreatment PSA level, T classification, and Gleason score were each independently highly significantly (P < 0.001) correlated with every endpoint. Pretreatment PSA level was the most significant variable for rising PSA and local recurrence, and T classification was the most significant variable for metastatic relapse. Using relapse/rising PSA as the endpoint, the authors formulated a highly significant 6-tier prognostic grouping based on PSA, T classification, and Gleason score, as follows: Category I: T1/T2, PSA £ 4, and Gleason 2-6 (relapse rate, 6%); Category II: T1/T2, PSA £ 4 and Gleason 7-10, or PSA 4 to £ 10 and Gleason 2-7 (relapse rate, 30%); Category III: T1/T2, PSA to £ 10 and Gleason 8-10, or PSA 10 to £ 20 and Gleason < 8 (relapse rate, 40%); Category IV: T3/T4, PSA < 10 (relapse rate, 46%); Category V: T3/T4, PSA 10 to £ 20, and Gleason < 8 (relapse rate, 57%); Category unfavorable: any T, PSA > 20 and any Gleason, or PSA 10 to £ 20 and Gleason 8-10 (relapse rate, 88%).
Conclusions. The establishment of T classification and Gleason score as independent prognostic factors bridges an apparent gap between an older era and the current PSA era. PSA has supplemented, rather than supplanted, the utility of the traditionally established prognostic factors for clinically localized prostate carcinoma.
Multiple myeloma
Multiple myeloma is a disorder in which malignant plasma cells accumulate in the bone marrow and produce an immunoglobulin, usually monoclonal IgG or IgA. Common complications of overt multiple myeloma include recurrent bacterial infections, anemia, osteolytic lesions, and renal insufficiency. Multiple myeloma is responsible for about 1 percent of all cancer-related deaths in Western countries. Its epidemiologic pattern remains obscure, and its cause is unknown1.
Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia
Abstract
Methods. We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 µg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups.
Results. Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P = 0.011) and fewer documented infections (12 vs. 27, P = 0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups ($8,768 and $8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P = 0.049).
Conclusions. G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care.
Dose intensity for bolus versus infusion chemotherapy administration: review of the literature for 27 anti-neoplastic agents
Summary
Objective. To review the literature for selected antineoplastic drugs to analyze the relative DI and MTD for bolus vs. infusional administration schedules.
Methods. Clinical reports of bolus and infusional delivery of chemotherapeutic drugs in the categories of antimetabolites; alkylating agents; antibiotics; plant alkaloids and platinum analogues were collected focusing on phase I studies establishing the MTD per cycle and the DI. Infusional schedules were defined as continuous parenteral administration for more than 24 hours or, in some instances, daily bolus dosing for one hour for 3 to 5 days. Bolus schedules sere defined as administration over minutes up to 24 hours and also included daily dosing in some cases.
Results. For antimetabolites, the infusional schedule generally decreases the MTD and DI relative to bolus administration but for 5-FU, the MTD and DI both increase. For alkylating agents and the platinum analogues, the MTD and DI for bolus and infusional delivery are generally comparable; but infusional administration results in a slightly increased MTD for thiotepa and for ifosfamide, the MTD is increased depending upon the duration of the infusion. For the antibiotics and the plant alkaloids, the MTD and DI of infusional administration is variable related to the specific agent and the infusion duration and may be increased, decreased or comparable to the MTD of bolus schedules.
Conclusions. The MTD and DI for most cytotoxic agents administered by bolus versus infusional schedules is unpredictable and variable and is influenced by the infusion duration and the interval between treatment cycles (for example three versus four week intervals). The MTD and DI increase substantially with infusional delivery for thiotepa, 5-FU and VM26 (the latter in leukemia specifically) and decrease substantially for the antimetabolites FUDR, ara-C, methotrexate and 6MP. For most other agents and in all four drug categories, the MTD and DI are relatively comparable although for ifosfamide and topotecan, the duration of infusion determines whether the MTD and DI increases, decreases or stays the same relative to bolus administration. The use of cytokines may substantially change the MTD and DI especially for bolus administration since dose limiting toxicity is hematologic for many agents.
Diagnosis and treatment of major depression among people with cancer
Although depressive disorders are common among 20-25% of people with cancer, they are frequently unrecognized. Untreated depression in the presence of comorbid conditions may result in more frequent clinic visits, increased costs, extended hospitalization, and reduced compliance and quality-of-life. Oncology clinicians need not have psychiatric expertise to play a major role in the detection and treatment of depression and in the prevention of suicide. Using early detection and screening tools, the nurse can identify depressed patients and can collaborate in their treatment. Approximately 80-90% of depressed patients are effectively treated with psychotherapy, and/or pharmacologic, or somatic, interventions. Failure to diagnose or reluctance to treat depression among patients with cancer is a common error and can increase morbidity and mortality.
A multicentre, double-blind study comparing placebo, ondansetron and ondansetron plus dexamethasone for the control of cisplatin-induced delayed emesis
1 Royal Adelaide Hospital, Adelaide, Australia;
Summary
Patients and Methods. This was an international, multicentre, double-blind, randomised, -placebo-controlled, parallel group study. A total of 640 chemotherapy-naïve patients received ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. for the control of acute emesis prior to cisplatin (³ 70 mg/m2) on day 1. Patients who were not rescued or withdrawn on day 1 were to be randomised 24 hours after the start of cisplatin administration to one of four groups; group I placebo oral (p.o.), twice daily (bd) on days 2-6 (n = 125); group II ondansetron (8 mg p.o. bd) on days 2/3 followed by placebo (p.o. bd) on days 4-6 (n = 199); group III ondansetron (8 mg p.o. bd) on days 2-6
(n = 214); group IV ondansetron (8 mg p.o. bd) plus dexamethasone (4 mg p.o. bd) on days 2-6 (n = 66).
Results On day 1, 81% of patients had complete control of acute emesis, with 68% having no emesis and no nausea. Over days 2/3 and over days 2-6, significantly more patients receiving ondansetron plus dexamethasone (group IV) reported no emesis and no nausea (49% and 45%, respectively) compared to ondansetron alone (32% and 27%, respectively) or placebo (group I; 33% and 27%, respectively; P < 0.05 for all pairwise comparisons). There were no significant differences in the control of emesis over days 2/3, where 61% of patients had complete emetic control (0 emetic episodes) with ondansetron plus dexamethasone (group IV),54% with ondansetron (groups II + III) and 49% with placebo (group I). In the distribution of nausea grades, ondansentron plus dexamethasone (group IV) was significantly superior to ondansetron (groups II + III; P = 0.037) and placebo (group I; P = 0.013) over days 2/3. Over days 2-6 there were no significant differences in the control of emesis, however a comparison of the distribution of nausea grades over days 2-6 showed ondansetron plus dexamethasone (group IV) to be significantly superior to ondansetron (group III; P = 0.043) and placebo (group I; P = 0.024).
All treatments were well tolerated and no unexpected drug-related adverse events were reported. There were no differences in the overall incidence of adverse events between the active treatment groups or placebo. Constipation and headache, recognised side effects of 5-HT3 receptor antagonists, were the most commonly reported adverse events with the incidence of constipation with ondansetron alone (group III) being significantly greater than with placebo over days 2-6 (14% vs. 6%; P = 0.030).
Conclusions. In contrast to some previous investigations, in this study, ondansetron alone appears to have a minor role in the control of cisplatin-induced delayed emesis and nausea. In conclusion, the combination of oral ondansetron plus dexamethasone is superior to ondansetron and to placebo.
Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia
Abstract
Methods.: We performed a randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor (G-CSF) in afebrile outpatients with severe chemotherapy-induced neutropenia. We measured the number of days in the hospital, number of days the patient received parenteral antibiotics, and number of culture-positive infections.
Results. We randomly assigned 138 patients to receive G-CSF (n = 71) or placebo (n = 67). The median time to an absolute neutrophil count higher than 500 per cubic millimeter was significantly shorter for patients who received G-CSF (two days, vs. four days for the patients given placebo). However, there was no effect on the rate of hospitalization, number of days in the hospital, duration of treatment with parenteral antibiotics, or number of culture-positive infections.
Conclusions. Routine therapeutic application of G-CSF in afebrile patients with severe neutropenia can reduce the duration of neutropenia, but this does not appear to provide practical clinical benefit.
Physical activity and the risk of breast cancer
Abstract
Methods. During 1974 to 1978 and 1977 to 1983, a total of 25,624 women, 20 to 54 years of age at entry, enrolled in health surveys and answered questionnaires about leisure-time and work activity.
Results. During a median follow-up of 13.7 years, we identified 351 cases of invasive breast cancer among the 25,624 women in the cohort. Greater leisure-time activity was associated with a reduced risk of breast cancer, after adjustments for age, body-mass index (the weight in kilograms divided by the square of the height in meters), height, parity, and county of residence (relative risk, 0.63; 95 percent confidence interval, 0.42 to 0.95), among women who exercised regularly, as compared with sedentary women (P for trend = 0.04). In regularly exercising women, the reduction in risk was greater in pre-menopausal women, than in postmenopausal women, and greater in younger women (< 45 years at study entry) than in older women (³ 45 years) (relative risk, 0.38; 95 percent confidence interval, 0.19 to 0.79). In stratified analyses the risk of breast cancer was lowest in lean women (body-mass index, < 22.8) who exercised at least four hours per week (relative risk, 0.28; 95 percent confidence interval, 0.11 to 0.70). The risk was also reduced with higher levels of activity at work, and again there was a more pronounced effect among premenopausal than post-menopausal women.
Conclusions. Physical activity during leisure time and at work is associated with a reduced risk of breast cancer. (N Engl J Med 1997; 336: 1269-75.)
© 1997, Massachusetts Medical Society.
Nutritional support
The indications for providing nutrients by the enteral or intravenous route (nutritional support) are not well defined, and the efficacy of nutritional support in many circumstances is unproved. Nonetheless, nutritional support is widely used for several reasons: malnutrition is common in hospitalized patients1, 2, there is an association between malnutrition and increased morbidity3, 4 and mortality5, it seems intuitively likely that well-nourished patients will respond most favorably to treatment, nutritional support can be administered safely to most patients, and clinical trials indicate that it is beneficial in selected patients6-10.
Virtually all patients can be fed intravenously or enterally, because of the development of two important techniques: the infusion of hypertonic nutrient solutions by central venous catheterization and the intraluminal administration of specific enteral diets through a feeding tube. Both parenteral and enteral formulations can deliver all essential nutrients, and many patients who cannot eat normally live productive lives while being nourished exclusively by one or both of these routes. Although the justification for providing nutritional support has been to prevent or reverse the wasting of host tissue, the primary rationale for its use should be to improve clinical outcome.
Complications leading to surgery after breast implantation
Abstracts
Methods. We studied 749 women who lived in Olmsted County, Minnesota, and received a first breast implant at the Mayo Clinic between 1964 and 1991. We identified complications that occurred after the initial procedure and after any subsequent implantation. A complication was defined as a surgical procedure performed for any of the following reasons: capsular contracture; rupture of the implant; hematoma or bleeding; infection or seroma of the wound; chronic pain; extrusion, leakage, or sweating of the implant; necrosis of the nipple, areola, or flap; malfunction of the filler port of a tissue expander; and wound dehiscence.
Results. During follow-up (mean, 7.8 years; range, 0 to 25.8), 208 (27.8 percent) of the women underwent 450 additional implant-related surgical procedures. Ninety-one (20.2 percent) were anticipated, staged procedures or were done because the patient requested a size change or aesthetic improvement, and 359 procedures (79.8 percent) had at least one clinical indication (thus constituting a complication). Complications occurred in 178 (23.8 percent) of the 749 women and involved 274 (18.8 percent) of the 1454 breasts with implants and 321 (18.8 percent) of the 1703 implants. The most frequent problem was capsular contraction (131 women), followed by implant rupture (43 [5.7 percent]), hematoma (43), and wound infection (19). The rate of complications was significantly lower (P < 0.001) among women with cosmetic implants (6.5 percent at one year, 12 percent at five years) than among those who received implants after mastectomy for breast cancer (21.8 percent at one year, 34 percent at five years) or prophylactic mastectomy (17.3 percent at one year, 30.4 percent at five years).
Conclusions. Women who have had breast implantation frequently experience local complications during the subsequent five years. Complications were significantly less frequent among patients who received implants for cosmetic reasons than among those who received implants after mastectomy for cancer or for cancer prophylaxis.
Introduction
Interest in prognostic factors has been stimulated by the success of systemic adjuvant therapy for early-stage, operable cancer of the breast. Any feature of a tumor, or combination of features, that accurately indicates which patients are destined for recurrence and which are not is of considerable importance. Patients destined for recurrence can be selected for systemic adjuvant therapy, while patients who will not have a recurrence can be spared the morbidity of a treatment that offers no benefit. In addition, refinement of prognostic information facilitates improved clinical testing by ensuring comparability of treatment groups and providing markers to measure the success or failure of specific therapies.
The literature devoted to prognostic factors for breast cancer is extensive. Scientific reports are supplemented by a multitude of letters, reviews, and meta-analyses. Univariate and multivariate analyses are basic techniques. Variables are individually compared with measures of outcome, and those that are significantly related to outcome are used in multivariate analyses to determine if they have independent predictive value.These are the combined to form new prognostic categories.The mix of individual variables changes, however, and interrelationships are not always consistent.
Measures of outcome are multiple, and relationships to outcome are subject to change with duration of follow-up.
Confirmation of projected outcomes with prospective studies is largely lacking for newer variables. The complexities are such that computer models are needed for integration of information. Computerized neural networks that are designed to learn from new data and predict individual patient outcome are under development to assist clinicians in making decisions about clinical management.The purpose of this article is to review tumorrelated biologic factors of current interest and relate them to prognosis and treatment objectives.
Acute lymphoblastic leukemia (ALL) has served as a model for the cure of neoplasia by chemotherapy. Current treatment results in complete remissions in 80% to 90% of cases with long-term survival of 30% to 40%. Mature B cell and T cell ALL cases that previously had a poor prognosis are now viewed as favorable subgroups. Treatment regimens have evolved empirically into complex schemes, although few of the individual components have been rigorously tested in randomized trials. Maintenance therapy is a standard component of pediatric ALL, but its benefit has not been completely established in adults, although two trials which omitted maintenance are notable for short disease-free survival. Optimal consolidation and intensification therapy remains controversial with numerous trials suggesting benefit, but several randomized trials fail to confirm improved disease-free survival. Central nervous system prophylaxis is an integral step in treatment. Identification of subtypes of ALL with different prognosis and treatment requirements offers the potential to improve management and survival in ALL.
Prognostic factors in elderly acute lymphoblastic leukaemia
1 Service d’Hématologie Clinique;
2 Service d’Hématologie Biologique, et
3 Service de Cytogénétique, Hôpital Hôtel-Dieu, Paris,
France
A retrospective study was performed on 46 unselected acute lymphoblastic leukaemia (ALL) elderly patients aged 60 years or more. Only 50% of these patients were included in the EORTC cooperative clinical trials, thus confirming the important selection bias in most of the published series on elderly ALL patients. 43% of the elderly patients achieved a complete remission (CR). The median survival was 10 months and the 5-year overall survival was only 7.6 ± 4%. In multivariate analysis, W.H.O. performance status and peripheral blast counts at day 7 were found to significantly influence achievement of CR and survival. In patients with W.H.O. performance status ³ 2, 35% died during induction treatment versus 4% in patients with W.H.O. performance status < 2. Patients > 70 years old showed a marked drop of the CR rate (27%) compared to those aged 60-69 (67%), and a very high death rate during the induction period (38% versus 4%). This suggests that ALL protocol treatments should be proposed until 70 years in patients with good-performance status, whereas less intensive treatment should be offered to elderly patients with performance status ³ 2 and/or age ³ 70. Peripheral blast counts at day 7 may help to adjust the treatment during induction phase.
Paediatric oncology update
Acute lymphoblastic leukaemia
Many Enigmas continue to surround childhood acute lymphoblastic leukaemia (ALL). We still do not know what causes it, how long it takes to develop, how best to classify the different subtypes, or how best to use the therapeutic tools we currently have at our disposal. So the "Great Success Story" of paediatric oncology is far from complete. Current uncertainties about the disease can conveniently be considered in the three areas of aetiology, biology and therapy.
Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection
Abstract
Methods. We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkin’s lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte-macrophage colony-stimulating factor (GM-CSF; n = 94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n = 98).
Results. A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P = 0.56). There were no significant differences in overall or disease-free survival; median survival times were 35 weeks for patients receiving low-dose therapy (risk ratio for death in the standard-dose group, 1.17; 95 percent confidence interval, 0.84 to 1.63; P = 0.25). Toxic effects of chemotherapy rated grade 3 or higher occurred in 66 of 94 patients assigned to standard-dose therapy (70 percent) and 50 of 98 patients assigned to low-dose treatment (51 percent, P = 0.008). Hematologic toxicity accounted for the difference.
Conclusions. As compared with treatment with standard doses of cytotoxic chemotherapy (m-BACOD), reduced doses caused significantly fewer hematologic toxic effects yet had similar efficacy in patients with HIV-related lymphoma. Dose-modified chemotherapy be should be considered for most HIV-infected patients with lymphoma.
The treatment of adult acute myeloid leukemia
Induction therapy of acute myeloid leukemia (AML) with standard-dose chemotherapy will result in 52% to 72% of patients achieving a complete remission (CR) on bone marrow morphology. Newer agents that appear to improve the outcome of induction therapy are etoposide, idarubicin, and high-dose cytarabine. New studies are now required to define new induction combinations and the place of these and other promising new drugs in the treatment. Standard attenuated postremission therapy is required after standard induction to maintain remission. However, new intensified postremission therapies have significantly improved outcome in de novo AML. This development has required re-examination of the value of intensive treatment. There is now clear clinical evidence that a dose-response effect is present for cytarabine in AML. The optimal placement of intensified treatment and marrow transplantation requires further study. In the future, it is likely that new treatment strategies will be defined by identifying new prognostic subgroups. To identify new successful induction treatments in AML, more precise measures of CR are required including an attempt to define cytogenetic CR and molecular CR wherever it can be applied. A theoretical model of blast cell kill would suggest that remission duration may be a useful clinical end point to study the influence of new induction therapies on residual resistant leukemia.
Clinical correlates of elevated serum levels of interleukin-6 in patients with untreated Hodgkin’s disease
Background. Interleukin-6 (IL-6) is a potent immunomodulatory cytokine that may have pathogenetic significance in several malignancies. In addition, high IL-6 levels have been associated with a poor prognosis in multiple myeloma, nonHodgkin’s lymphoma, ovarian cancer, and renal cancer, as well in advanced Hodgkin’s lymphoma. In this study, we analyzed IL-6 levels in newly diagnosed Hodgkin’s disease and determined clinical correlates of elevated levels.
Patients and methods. Using a sensitive enzyme-linked immunosorbent assay (lower limit of sensitivity = 0.35 pg/mL) we measured IL-6 levels in sera from 33 healthy controls and 65 untreated patients with Hodgkin’s disease.
Results. Interleukin-6 levels in the Hodgkin’s patients (median 2.7 pg/mL; range < 0.35 to 38.4 pg/mL) were significantly higher than in the controls (median < 0.35 pg/mL; range < 0.35 to 1.87 pg/mL; P < 0.0001). Interleukin-6 levels were also higher in males (P = 0.03) and in patients with bulky disease (P = 0.026) or advanced Ann Arbor stage (P = 0.017). In addition, serum levels of IL-6 also showed direct linear correlations with the erythrocyte sedimentation rate (r = 0.64, P = 0.0007), platelet count (r = 0.53, P < 0.0001), leukocyte count (r = 0.36, P = 0.003), and ß2-microglobulin level (r = 0.4, P = 0.0012); and an inverse linear correlation with serum albumin level (r = -0.43, P = 0.0003). In the 10 patients tested who had elevated serum IL-6 levels pretherapy and who achieved complete remission, serum IL-6 values decreased at the time of remission to the range found in healthy controls.
Evaluation of the revised European-American lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma
The Revised European-American Lymphoma (REAL) classification has been criticized for its emphasis on the unproven clinical relevance of immunophenotype. A worse prognosis for peripheral T-cell non-Hodgkin’s lymphomas (PTCLs) has been inconsistently reported in part because the definition of PTCL has been imprecise (eg, T-cell-rich B-cell non-Hodgkin’s lymphomas [TCRBCLs] have been misdiagnosed as PTCLs in the past) and because its correlation with other known prognostic factors has not been studied by multivariate analysis. We analyzed six protocols from 1984 to 1995 with Working Formulation intermediate grade and immunoblastic lymphomas (exclusive of mantle cell) and selected only those cases in which immunophenotyping was performed and was conclusive. Of a total of 560 evaluable patients, 68 were PTCLs (12%) and the remaining 492 (88%) were B-cell non-Hodgkin’s lymphomas, including 16 TCRBCLs (3% of total). The 5-year failure-free survival (FFS) for PTCLs and B-cell large-cell lymphomas (BCLCLs) is 38% and 55%, respectively (P < .0001) and the 5-year overall survival (OS) is 39% and 262%, respectively (P < .001). The M.D. Anderson prognostic tumor score (MDATS) and International Prognostic Index (IPI) for all patients was calculated. With MDATS of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 56% and 69%, respectively (P = .01), and the 5-year OS is 64% and 77%, respectively (P = .06). With MDATS of greater than 2 (poor prognosis), 5-year FFS for PTCL and BCLCL is 26% and 38%, respectively (P = .03) and the 5-year OS is 24% and 41%, respectively (P = .02). With an IPI of less than 3 (good prognosis), the 5-year FFS for PTCL and BCLCL is 49% and 64%, respectively (P = .001), and the 5-year OS is 55% and 71%, respectively (P = .013). With an IPI greater than 2 (poor prognosis), the 5-year FFS for PTCL and BCLCL is 11% and 35%, respectively (P = .044), and the 5-year OS is 10% and 40%, respectively (P = .011). Multivariate analysis shows that MDATS, IPI, and T-cell phenotype are totally independent and are the most significant predictors of FFS and OS. The 68 PTCLs include 45 PTCLs unspecified, 10 Ki-1 anaplastic (ALCL), 8 angioimmunoblastic, and 5 angiocentric lymphomas. Angiocentrics were usually refractory (1 of 5 remissions only). ALCL rarely relapsed late. We conclude that the immunophenotypic basis of the REAL classification is clinically relevant and that, although other prognostic features also influence outcome, the T-cell phonotype still remains an independent and significant prognostic factor.
Definitive irradiation in the treatment of Hodgkin’s disease
Analysis of outcome, prognostic factors, and long term complications
1 Department of Radiation Oncology, Bowman Gray School of Medicine, Winston-Salem,
North Carolina;
Background. In the curative treatment of Hodgkin’s disease, many institutions give doses above 40 Gray (GY). To assess the effectiveness of treating patients with 35 Gy, data from a single institution regarding survival, prognostic factors, patterns of failure, and secondary complications were reviewed.
Methods. Data for a total of 172 patients with Hodgkin’s disease were reviewed. All patients received definitive irradiation between 1971 and 1994. Median follow-up was 110 months. Kaplan-Meier methods were used to estimate survival, relapse-free survival, and complication rates.
Results. Relapse-free survival was 83% at 5 years and 76% at 10 years. He only two prognostic factors related to relapse-free survival were the stage of disease and the number of sites. The involved infield control rate was 96%. The 10-year estimates of hypothyroidism and second malignancies were 14% and 10%, respectively.
Conclusions. Doses of 35 Gy are adequate for treating Hodgkin’s disease. The stage of disease and the number of sites are predictive of relapse-free survival. The incidence of late complications necessitates long term surveillance of these patients.
High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma
Abstract
Purpose We investigated the associations between the intake of calcium and vitamin D and the occurrence of colorectal cancer.
Methods. Ninety-eight eligible patients with diffuse large-cell lymphoma of the B-cell type were randomly assigned to receive either MACOP-B (50 patients) or high-dose sequential therapy (48 patients). If the assigned treatment failed, the study design allowed patients to cross over to the other treatment group.
Results. After a median follow-up of 55 months, the patients given high-dose sequential therapy, as compared with those treated with MACOP-B, had significantly higher rates of complete response (96 percent vs. 70 percent, P = 0.001), freedom from disease progression (84 percent vs. 49 percent, P < 0.001), freedom from relapse (88 percent vs. 70 percent, P = 0.055), and event-free survival (76 percent vs. 49 percent, P = 0.004). The difference in overall survival at seven years, which also favored the group assigned to high-dose sequential therapy, was marginally significant (81 percent vs. 55 percent, P = 0.09).
Conclusions. High-dose sequential therapy is superior to standard-dose MACOP-B for patients with diffuse large-cell lymphoma of the B-cell type.
Prolonged survival of 2 years or longer for patients with disseminated melanoma
1 Dermatological Clinic, Inselspital, Berne, Switzerland;
Background. Once melanoma has metastasized to distant sites, the prognosis is usually poor, showing an overall median survival of 6-8 months. Long term survival is extremely rare, and there is still controversy concerning the prognostic significance of therapeutic modalities. The aim of the current study was to identify important prognostic factors associated with Stage IV melanoma.
Methods. The current study was based on data for 3258 melanoma patients, for whom clinical, pathologic, and long term follow-up information was recorded during the period 1976-1996 at the Eberhard-Karls-University in Tuebingen, Germany. The attainment of 2 years’ or longer survival time by patients with disseminated melanoma was addressed, and a multivariate analysis of related prognostic factors was performed by logistic regression.
Results. Four hundred forty-two patients (13.6%) developed distant metastasis. The median survival time was 7 months, and the 2-year, 5-year, and 10-year survival rates were 11.9%, 6.7%, and 4.7%, respectively. Forty-five patients had prolonged survival of 2 years or longer. Significantly more females belonged to the group of long term survivors (P = 0.0186). Of the modalities of therapy given, only surgery was associated with prolonged survival (P < 0.0001). Primary metastasis to the skin (P = 0.006), the brain (P = 0.015), more than a single metastatic site (P = 0.002), and Karnofsky performance status of less than 80 (P = 0.0035) were significantly related to short term survival. In addition, subsequent development of two or more new metastatic sites was also associated with short term survival (P = 0.0025).
Conclusions. In the current analysis, prolonged survival of 2 years or longer for patients with disseminated melanoma was shown to depend on gender, site of primary metastasis, number of metastatic sites, and Karnofsky performance status. Of the modalities of therapy given, only surgery significantly influenced survival. However, in a small percentage of patients, long term complete remission was achieved with chemotherapy alone or in combination with surgery, suggesting that such regimens might be curative in selected cases.
Anti-HTLV-1 antibody positive cutaneous T-cell lymphoma
1 Department of Dermatology, Keio University School of Medicine, Tokyo, Japan;
Background. Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of the mature helper T-lymphocyte. Human T-lymphotropic virus type 1 (HTLV-1) has been shown to be the cause of this neoplasm. Recently, however, the HTLV-1 genome has been found in some patients with cutaneous T-cell lymphoma (CTCL), which suggests a causal relation of HTLV-1 to CTCL. Thus, the relation between the HTLV-1 genome and CTCL, as well as the difference between ATLL and CTCL, have come into question.
Methods. The authors examined two patients with CTCL whose serum anti-HTLV-1 antibodies were constantly positive. The Southern blot technique, inverse polymerase chain reaction (IPCR), and polymerase chain reaction (PCR) with four sets of primers for gag, pol, env, and pX regions of HTLV-1 were used to clarify the distinctions between ATLL and CTCL.
Results. Clinically, one patient presented with multiple subcutaneous nodules with involvements of the internal organ, and the other patient was typical for mycosis fungoides. No integration of HTLV-1 DNA was detected by IPCR or the Southern blot technique in either patient. PCRs with the four sets of primers were all found to be positive for HTLV-1 except one.
Conclusions. The authors conclude that ATLL should be differentiated from CTCL in view of the responsibility of HTLV-1 for promoting or maintaining CTCL.
Risk of testicular cancer in cohort of boys with cryptorchidism
Abstract
Design. Cohort study.
Settings. Hospital for Sick Children, Great Ormond Street, London.
Subjects. 1075 boys with cryptorchidism treated by orchidopexy or hormones at the hospital during 1951-64.
Main outcome measures. Relative risk of testicular cancer in the cohort compared with men in the general population.
Results. 12 testicular cancers occurred in 11 of the patients during follow up to mid-1990 (relative risk of cancer in males with cryptorchidism = 7.5 (95% confidence interval 3.9 to 12.8). The relative risk fell significantly beyond 15 years after orchidopexy but did not decrease with younger age at orchidopexy. Risk was significantly raised in testes that had had biopsy samples removed during orchidopexy (relative risk = 66.7 (23.9 to 143.3) compared with a testis in a man in the general population) and was significantly greater in these testes than in undescended testes that had not had biopsy samples taken at orchidopexy (6.7 (2.7 to 13.5)). No reasons for biopsy or distinguishing clinical aspects of the testes that had had biopsy samples taken and later developed malignancies were evident in the case notes. No histological abnormalities were evident at initial biopsy except in one testis that had features of dysgenesis.
Conclusion. Biopsy seems to be a stronger risk factor for testicular cancer than any factor previously identified. The trauma of open biopsy may contribute substantially to risk of malignancy or the testes may have been selected for biopsy on the basis of clinical factors predictive of malignancy but not mentioned in the case notes.
Mantle cell lymphoma: a clinicopathologic study of 80 cases
Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS mong these groups was identical. Increased mitotic activity (> 20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation (11;14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.
A multiple prognostic index predictive of disease outcome after irradiation for clinically localized prostate carcinoma
1 Division of Radiation Oncology, Mayo Clinic and Mayo Foundation, Rochester,
Minnesota;
Background. This investigation was conducted to identify independent pretherapy disease-related factors associated with disease outcome in patients with clinically localized carcinoma of the prostate (CaP) and to develop models that incorporated relevant covariates for estimating the risk of disease relapse after irradiation (RT).
Methods. The outcome of 500 patients treated only with RT between March 1987 and June 1993 for clinical Stages T1-4N0,XM0 CaP was evaluated. The risk of disease relapse as a function of individual prognostic variables, and combinations thereof, was determined using logistic regression.
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. With a median follow-up of 43 months (range, 4-103 months), 69 patients (14%) had clinical evidence of local recurrence (27 patients), regional lymph node relapse (4 patients), or metastatic relapse (38 patients) within 5 years of RT. Forty additional patients (8%) had biochemical relapse based solely on the post-RT serum prostate specific antigen (PSA) profile. Clinical tumor stage (P = 0.0006), Gleason score (P = 0.001) of the diagnostic biopsy specimen, and pretherapy PSA (P < 0.0001) were associated with disease relapse. The risk of any relapse within 5 years of RT was determined and graphically displayed as risk estimate plots for combinations of these pretherapy prognostic variables.
Conclusion. The combination of pretherapy clinical tumor (T) stage, Gleason score, and PSA level can be used to obtain improved estimates of the risk for disease relapse in patients treated solely with RT for clinically localized CaP. Risk estimate plots of this type may facilitate exchange of therapeutic outcome information, be instrumental in pretherapy decision-making for the new patient with this condition, and aid in the selection of patients for future studies.
Fifteen-year survival in prostate cancer
A prospective, population-based study in sweden
Objective. To describe the natural history of initially untreated early-stage prostate cancer. A key secondary objective was to calculate long-term survival rates by stage, grade, and age at diagnosis.
Design. Prospective cohort study.
Setting. Population-based in 1 county of Sweden, without screening for prostate cancer.
Patients. A group of 642 patients with prostate cancer of any stage, consecutively diagnosed between 1977 and 1984 at a mean age of 72 years with complete follow-up to 1994.
Main outcome measures. Proportion of patients who died from prostate cancer, and 15-year survival (with 95% confidence interval [CI]), corrected for causes of death other than prostate cancer.
Results. In the entire cohort, prostate cancer accounted for 201 (37%) of all 541 deaths. Among 300 patients with a diagnosis of localized disease (T0-T2), 33 (11%) died of prostate cancer. In this group, the corrected 15-year survival rate was similar in 223 patients with deferred treatment (81%; 95% CI, 72%-89%) and in 77 who received initial treatment (81%; 95% CI, 67%-95%). The corrected 15-year survival was 57% (95% CI, 45%-68%) in 183 patients with locally advanced cancer (T3-T4) and 6% (95% CI, 0%-12%) in those 159 who had distant metastases at the time of diagnosis.
Conclusion. Patients with localized prostate cancer have a favorable outlook following watchful waiting, and the number of deaths potentially avoidable by radical initial treatment is limited. Without reliable prognostic indicators, an aggressive approach to all patients with early disease would entail substantial overtreatment. In contrast, patients with locally advanced or metastatic disease need trials of aggressive therapy to improve their poor prognosis.
Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma
Background. Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial.
Methods. Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated.
Results. Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis.
Conclusions. The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.
Controversies in prostate cancer screening
The current debate regarding early detection and aggressive treatment of prostate cancer is fueled by the absence of controlled studies defining the risks and benefits of prostate cancer screening, and by the lack of adequately powered trials demonstrating the benefit of curative treatment for early-stage prostate cancer. Pending the results of clinical trials in 10 to 15 years, advocates of early detection of prostate cancer with digital rectal examination and prostate-specific antigen have compared prostate cancer screening with the effective strategy of breast cancer screening, implying that prostate cancer screening should similarly reduce cancer mortality. They have also cited the high burden of disease, the acceptable operating characteristics of digital rectal examination and prostate-specific antigen, a stage shift among cases detected by screening, and the theoretical curability of early-stage disease as sufficient reasons to proceed with screening. These arguments, however, are reminiscent of earlier arguments in favor of lung cancer screening with chest x-ray examination and sputum cytology, a practice ultimately proven ineffective in clinical trials. We reviewed published articles on lung and prostate cancer screening and identified many parallels. While prostate cancer screening may one day prove effective, analogies between the current prostate cancer screening controversy and the older lung cancer screening debate should inject some caution regarding widespread dissemination of prostate cancer screening without experimental evidence that such screening does more good than harm.
Malignant melanoma: Mayo Clinic experience
To present the Mayo Clinic experience with treatment of melanoma of the trunk and extremities, we reviewed previous Mayo Clinic studies on the management of malignant melanoma and summarized the survival data and treatment-related outcome. A prospective trial involving elective lymph node dissection in 171 patients with malignant melanoma showed no advantage in overall survival and disease-free survival in the group whose nodes were removed. In an assessment of the treatment variables, a Cox stepwise multiple regression analysis showed a strong correlation of lesion thickness and level of invasion with survival. Another study of 535 patients with melanomas that involved the trunk and extremities, who were treated at the Mayo Clinic between 1971 and 1980, showed an overall survival of 83%. Patients with thin lesions (less than 0.76 mm thick) had a 98% 5-year survival, whereas patients with lesions 4 mm thick or thicker had only a 45% 5-year survival. Because the Mayo Clinic prospective randomized study showed no benefit for patients with melanoma who undergo immediate or delayed lymphadenectomy in the trunk and extremities, we do not perform elective lymph node dissection; however, close follow-up of patients is instituted, and lymph node dissection is performed when nodal involvement is first suspected.
Malignant melanoma: an emerging and preventable medical catastrophe
The natural history of malignant melanoma, including the diagnosis, prognosis, and treatment options, is reviewed in an attempt to formulate appropriate management strategies. Awareness on the part of clinicians is important, inasmuch as early detection of malignant melanoma offers the best chance for improved survival. Most lesions are excised with a margin of 1 to 3 cm, and follow-up assessment intervals are based on the depth of the primary lesion. Follow-up usually consists of a medical history, physical examination, chest roentgenography, and hematologic and chemistry profiles. Routine use of sophisticated imaging studies is unnecessary because the yield from such an approach has been low. Patients with melanomas thicker than 1.6 mm and those with histologic evidence of involvement of regional lymph nodes are at risk for development of disseminated disease and may be candidates for adjuvant therapy. In patients with severe weight loss and poor nutrition because of advanced disease, analgesic agents, stool softeners, and appetite enhancers are palliative measures that should be considered.
Malignant melanoma: basic approach to clinicopathologic correlation
To provide an overview of the clinicopathologic correlation of the various types of malignant melanoma, we describe and illustrate the four major types of these tumors and discuss the concept of microstaging for the prognostic evaluation of melanoma. The four major types of malignant melanoma are lentigo maligna melanoma, acral lentiginous melanoma, superficial spreading melanoma, and nodular melanoma. Lentigo maligna melanoma has irregular margins and usually occurs on sunlight-exposed skin in elderly patients. Acral lentiginous melanoma occurs on the hands and feet; it often demonstrates massive invasion when the vertical growth phase occurs. Among Caucasians, superficial spreading melanoma, which affects the trunk and extremities, is the most common malignant melanoma. These lesions are often variegated in color. Nodular melanomas are deeply pigmented and enlarge rapidly. For microstaging of malignant melanoma, determining Clark’s level of tumor invasion or Breslow’s thickness (from the top of the granular cell layer of the epidermis to the deepest extension of the tumor) is useful for assessment of prognosis. Establishing a definite diagnosis of malignant melanoma is feasible through clinicopathologic correlation. Microscopic measurement of the deepest levels of melanoma involvement in the skin provides a useful indication of the associated prognosis.
Dermatopathologic variants of malignant melanoma
An appropriate biopsy is the pivotal procedure that facilitates accurate histopathologic diagnosis of a pigmented skin lesion. Excisional skin biopsy is the method of choice for removing a suspected malignant melanoma. More than 95% of malignant melanomas that involve the skin belong to one of the four most common clinicopathologic categories: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma. A small but important group of cutaneous melanomas can be classified as unusual variants. Many of these unusual variants have a distinct histopathologic appearance; they include desmoplastic melanoma, neurotropic melanoma, pedunculated melanoma, metastatic melanoma, amelanotic melanoma, melanoma arising within a benign nevus, regressing (“invisible”) melanoma, and balloon cell melanoma. Other lesions may simulate malignant melanoma histopathologically. Immunohistochemical stains, such as S-100 protein, vimentin, keratin, and HMB-45, are useful for distinguishing these lesions from true melanoma.
Postsurgical adjuvant therapy for melanoma
1 Department of Dermatology, Catholic University, Rome, Italy;
Background. Early surgical intervention is still the most successful therapy fot patients with melanoma. The results obtained with medical therapies are still quite disappointing, with better results observed in soft tissue and lymph node metastasis. There currently is no standardized adjuvant therapy for primary melanoma. On the basis of the activity demonstrated in vitro against melanoma cell lines and the results obtained in many clinical trials in patients with advanced melanoma, the authors chose to study the use of recombinant interferon-a (IFN-a) as adjuvant therapy for patients with Stage I and Stage II melanoma.
Methods. A randomized multicenter trial based on the use of recombinant IFN-a-2b for 3 years at the dose of 3 UM given intramuscularly 3 times a week for a period of 6 months with a 1-month interval between cycles was conducted in Stage I and Stage II melanoma patients (using the American Joint Committee on Cancer classification). The efficacy of this treatment was evaluated calculating the incidence of recurrence after 3 and 5 years.
Results. Results were collected at the end of the treatment period and after 5 years of follow-up for a smaller number of patients. Statistical evaluation showed a significant difference between treated patients and untreated controls with regard to progression of the disease. In particular, IFN-a appears to be more effective in patients with worse prognosis lesions.
Conclusions. IFN-a appears to be effective as adjuvant therapy for high risk melanoma patients and the risk/benefit ratio appears to be very favorable. The authors’ next goal is to separate those patients who might benefit from adjuvant therapy from those who are cured after the surgical intervention only.
Clinical trials in relapsed prostate cancer: defining the target
A re-examination of the methods of developing new treatments for patients with prostate cancer whose disease has progressed during hormone therapy is necessitated by the following: 1) the impact of prostate-specific antigen (PSA) testing on patient selection, 2) the increasing number of studies using noncytotoxic approaches, and 3) the lack of validated methods to report outcomes. PSA monitoring after primary therapy has increased the number of patients referred for therapy with a rising value in this marker or an asymptomatic change in a radionuclide bone scan as the only manifestation(s) of relapse. The development of drugs for this population of patients presents a unique challenge because the classical criterion used to assess efficacy in the phase II setting, i.e., the presence of objective changes in measurable disease sites, frequently does not apply. Sicne no approach has been proven to prolong survival, the highest priority must be placed on developing new therapies. Standardizing the methods for evaluating treatments is also essential so that promising strategies are pursued and inactive therapies are not developed further.
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Revista Brasileira de Cancerologia - Volume 44 n°1 Jan/Fev/Mar 1998