Cancer-related anaemia requires higher doses of epoetin alfa than chronic renal failure replacement therapy.
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Anemia↗
Biomedical subjects
L M Itri
Publications and source records attributed to L M Itri.
Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury.
Erythropoietin (EPO), recognized for its central role in erythropoiesis, also mediates neuroprotection when the recombinant form (r-Hu-EPO) is directly injected into ischemic rodent brain. We observed abundant expression of the EPO receptor at brain capillaries, which could provide a route for circulating EPO to enter the brain. In confirmation of this hypothesis, systemic administration of r-Hu-EPO before or up to 6 h after focal brain ischemia reduced injury by approximately 50-75%. R-Hu-EPO also ameliorates the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate. Given r-Hu-EPO's excellent safety profile, clinical trials evaluating systemically administered r-Hu-EPO as a general neuroprotective treatment are warranted.
Animals↗
Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition.
PURPOSE: This survey was designed to confirm the prevalence and duration of fatigue in the cancer population and to assess its physical, mental, social, and economic impacts on the lives of patients and caregivers. Patients and Methods. A 25-minute telephone interview was completed with 379 cancer patients having a prior history of chemotherapy. Patients were recruited from a sample of 6, 125 households in the United States identified as having a member with cancer. The median patient age was 62 years, and 79% of respondents were women. Patients reporting fatigue at least a few times a month were asked a series of questions to better describe their fatigue and its impact on quality of life. RESULTS: Seventy-six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis. Ninety-one percent of those who experienced fatigue reported that it prevented a "normal" life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest/ relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations. CONCLUSIONS: Cancer-related fatigue is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.
Adult↗
Optimal hemoglobin levels for cancer patients.
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Adult↗
Chemotherapy-induced anemia in adults: incidence and treatment.
Anemia is a common complication of myelosuppressive chemotherapy that results in a decreased functional capacity and quality of life (QOL) for cancer patients. Severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia in patients receiving chemotherapy has traditionally been managed conservatively on the basis of the perception that it was clinically unimportant. This practice has been reflected in the relative inattention to standardized and complete reporting of all degrees of chemotherapy-induced anemia. We undertook a comprehensive review of published chemotherapy trials of the most common single agents and combination chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults to characterize and to document the incidence and severity of chemotherapy-induced anemia. Despite identified limitations in the grading and reporting of treatment-related anemia, the results confirm a relatively high incidence of mild-to-moderate anemia. Recent advances in assessing the relationships of anemia, fatigue, and QOL in cancer patients are providing new insights into these closely related factors. Clinical data are emerging that suggest that mild-to-moderate chemotherapy-induced anemia results in a perceptible reduction in a patient's energy level and QOL. Future research may lead to new classifications of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. Perceptions by oncologists and patients that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient and as research provides further insights into the relationships between hemoglobin levels, patient well-being, and symptoms.
Adult↗
Cancer-related fatigue: guidelines for evaluation and management.
Fatigue is a highly prevalent condition among cancer patients. Although most cancer patients report that fatigue is a major obstacle to maintaining normal daily activities and quality of life, it is seldom assessed and treated in clinical practice. Few studies have explored its epidemiology, possible etiologies, or management. Cancer-related fatigue, which recently was accepted as a diagnosis in the International Classification of Diseases 10th Revision-Clinical Modification, reduces physical, psychological, and social functioning and results in significant distress for patients and caregivers. Adequate evaluation of fatigue must do more than simply assess severity. The assessment should clarify other characteristics, determine the degree to which fatigue interferes with the activities of daily living, and identify potential causes, including the underlying disease, disease treatments, intercurrent systemic disorders, psychological disorders, and other conditions. Possible primary therapies include modification of the patient's drug regimen, correction of metabolic abnormalities, and pharmacologic treatments for anemia (e.g., epoetin alfa), depression, or insomnia. Other symptomatic interventions include specific drug treatments, exercise, modification of activity and rest patterns, cognitive therapies, sleep hygiene approaches, and nutritional support. Pharmacologic approaches, which are supported by limited studies and growing clinical experience, include psychostimulant drugs, corticosteroids, and possibly other therapies. Although additional research is needed to further identify the causes and corresponding treatment of fatigue, practitioners should routinely assess and treat patients who may benefit from currently identified interventions, because fatigue can profoundly undermine the quality of life of patients with cancer.
Depression↗
Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition.
Although fatigue is the most common symptom reported by cancer patients and has serious adverse effects on quality of life, it remains poorly understood. A survey was designed to characterize the epidemiology of cancer-related fatigue from the perspectives of the patient, primary caregiver, and oncologist. A telephone survey included 419 cancer patients recruited from 100,000 randomly selected households nationwide. Patients provided access to 200 primary caregivers (usually family members) who were also interviewed by telephone. In a separate mail survey, 197 of 600 randomly sampled oncologists (unrelated to the patients) responded to a questionnaire that assessed perceptions and attitudes concerning fatigue in cancer patients who had received chemotherapy or radiotherapy and their caregivers. The median patient age was 65 years, and the principal cancer diagnoses were breast (females) and genitourinary (males). Fifty-nine percent of the patients had received chemotherapy, 63% radiation therapy, and 24% both; 20% of patients received their last treatment within 6 weeks, 31% within 7 weeks to 1 year, and 49% more than 1 year ago. More than three quarters of patients (78%) experienced fatigue (defined as a general feeling of debilitating tiredness or loss of energy) during the course of their disease and treatment. Thirty-two percent experienced fatigue daily, and 32% reported fatigue significantly affected their daily routines. Caregivers reported observing fatigue in 86% of the index patients, and oncologists perceived that 76% of their patients experienced fatigue. Although oncologists believed that pain adversely affected their patients to a greater degree than fatigue (61% v 37%), patients felt that fatigue adversely affected their daily lives more than pain (61% v 19%). Most oncologists (80%) believed fatigue is overlooked or undertreated, and most patients (74%) considered fatigue a symptom to be endured. Fifty percent of patients did not discuss treatment options with their oncologists, and only 27% reported that their oncologists recommended any treatment for fatigue. When used, treatments for fatigue were generally perceived by patients and caregivers to be successful. These data confirm the high prevalence and adverse impact of cancer-related fatigue, although it is seldom discussed and infrequently treated. For patients and oncologists, improving the quality of life of cancer patients requires a heightened awareness of fatigue, a better understanding of its impact, and improve communication and familiarity with interventions that can reduce its debilitating effects.
Aged↗
Cancer chemoprevention.
Encouraging results from several recent trials have increased interest in the potential of chemoprevention in reducing the incidence of cancer. Treatment with 13-cis-retinoic acid has reversed oral leukoplakia, a premalignant lesion, and prevented the development of second primary carcinomas of the head and neck. Tamoxifen has proven effective in preventing both the recurrence of breast cancer and the development of new tumors in the contralateral breast, and is being tested in high-risk patients who have not yet developed disease. The results of the Physicians' Health Study, which demonstrated the effectiveness of aspirin in reducing heart attacks, already have been incorporated into health care practice, while the component investigating the effect of beta carotene on the incidence of cancer still is underway. These studies demonstrate the importance of careful design if chemoprevention trials are to yield convincing data.
Antineoplastic Agents↗
The interferons.
In the 10 years since the interferons (IFN) entered large-scale clinical trials, much has been learned much about their uses as single agents. alpha-IFN, the most widely studied, has shown antitumor and antiviral efficacy against various tumors and tumor-related viruses; it has been approved by the Food and Drug Administration for the treatment of patients with hairy cell leukemia, acquired immune deficiency syndrome-related Kaposi sarcoma, and condylomata acuminata. Although IFN are effective as single agents in certain clinical situations, increasing experience with these cytokines suggests that their greatest therapeutic potential may be in combination with other biologic response-modifying, cytotoxic, or antiviral drugs. Trials combining alpha-IFN with 5-fluorouracil to treat colorectal carcinoma or with zidovudine to treat acquired immune deficiency syndrome have shown the significant impact that IFN administered in conjunction with other carefully selected agents can have. To design the most effective combination regimens, better preclinical models that clarify the mechanisms of action of IFN and define their biochemical interactions with other agents are needed.
Antineoplastic Combined Chemotherapy Protocols↗
13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin.
BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.
Aged↗
Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid).
BACKGROUND AND METHODS: Patients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent. RESULTS: Eleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-alpha. As patients entered complete remission, the expression of the abnormal RAR-alpha message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved. CONCLUSIONS: Tretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease.
Administration, Oral↗
Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia.
Although highly active in hairy cell leukemia (HCL), interferons (IFN) are not curative in this disease; current data indicate that prolonged IFN therapy will be necessary to control disease in the majority of patients. We previously observed acquired IFN resistance in association with neutralizing IFN-alpha 2a antibodies in small numbers of patients with HCL. This finding suggests that the requisite long-term therapy may be compromised if there is an increasing incidence over time of neutralizing antibodies. We performed a follow-up study of IFN antibodies in our patients receiving continuous IFN therapy. All 16 patients who were previously antibody negative remained so. Surprisingly, all nine patients who previously had non-neutralizing IFN antibodies became antibody negative after a median of 14.5 months. Moreover, 3 of 10 patients who had neutralizing antibodies became antibody negative and five had only non-neutralizing antibodies a median of 10 months from the time neutralizing antibody had first been detected. Only two patients had persisting neutralizing antibodies. Inhibition of neopterin synthesis, inhibition of generation of 2', 5' oligoadenylate synthetase activity, and inability to detect IFN in serum after subcutaneous injection of IFN-alpha 2a was observed only in the one patient tested with neutralizing IFN antibodies confirming that these antibodies have functional significance in vivo. We conclude that, although neutralizing IFN antibodies inhibit the effectiveness of IFN in vivo, these antibodies are produced only transiently during long-term therapy. The long-term effectiveness of this drug will not likely be affected in most patients by neutralizing antibody.
Antibodies↗
Interferon-alpha 2a in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma.
In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.
Acquired Immunodeficiency Syndrome↗
Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck.
BACKGROUND: Patients with head-and-neck cancers who are free of disease after local therapy remain at high risk for both recurrent and second primary tumors. Retinoids have proved efficacious in the treatment of premalignant oral lesions and are promising agents for the prevention of epithelial carcinogenesis. METHODS: We prospectively studied 103 patients who were disease-free after primary treatment for squamous-cell cancers of the larynx, pharynx, or oral cavity. After completion of surgery or radiotherapy (or both), these patients were randomly assigned to receive either isotretinoin (13-cis-retinoic acid) (50 to 100 mg per square meter of body-surface area per day) or placebo, to be taken daily for 12 months. RESULTS: There were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers. However, the isotretinoin group had significantly fewer second primary tumors. After a median follow-up of 32 months, only 2 patients (4 percent) in the isotretinoin group had second primary tumors, as compared with 12 (24 percent) in the placebo group (P = 0.005). Multiple second primary tumors occurred in four patients, all of whom were in the placebo group. Of the 14 second cancers, 13 (93 percent) occurred in the head and neck, esophagus, or lung. CONCLUSIONS: Daily treatment with high doses of isotretinoin is effective in preventing second primary tumors in patients who have been treated for squamous-cell carcinoma of the head and neck, although it does not prevent recurrences of the original tumor.
Adult↗
Interferon combinations in cancer therapy.
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Combined Modality Therapy↗
Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant interferon-alpha 2a.
In clinical trials with a range of doses of recombinant interferon-alpha 2a, we observed a 25% overall incidence of neutralizing antibody development. Careful data analysis did not reveal a relationship between antibody development and therapeutic response. Of 752 patients evaluable for antibody development and clinical response, 31% of the antibody-positive patients and 28% of the antibody-negative patients had therapeutic responses. Although the formation of anti-IFN antibodies seems to be associated with most IFN preparations, incidence and clinical significance have been difficult to determine for a number of reasons. Different assays with differing sensitivities for the detection of IFN antibodies have been utilized in different studies. Additionally, important clinical variables that affect antibody development have often not been carefully controlled or analyzed. The relationship between antibody development and multiple related factors, such as route of administration, dose regimen, cumulative dose, duration of treatment, and the underlying disease, requires clarification. Initial analyses suggest that the median time to antibody development may vary with the dose regime and cumulative dose, as well as the route of administration. Carefully designed prospective studies controlling for influential clinical variables and utilizing standardized assay techniques are required for a meaningful analysis of the antigenic potential of all therapeutic protein products.
Antibodies↗
Safety of pregnancy after discontinuation of isotretinoin.
Isotretinoin (13-cis-retinoic acid, Accutane) increases the risk of major congenital malformations in infants exposed to isotretinoin during pregnancy. However, there have been no epidemiologic reports to date on the effect of a subsequent pregnancy after discontinuation of isotretinoin. This article describes our analysis of pregnancy case reports from patients in whom conception occurred after isotretinoin treatment had been discontinued. Based on the 88 prospectively ascertained cases, the incidence rate of both spontaneous and missed abortions from all pregnancies was 9.1% (eight patients), and the incidence rate of congenital malformation among the live births was 5.0% (four patients). The incidence rates for both these outcomes were not significantly different from the rates reported for women of reproductive age in the general population. In addition, the malformations reported were not characteristic of retinoic acid-induced congenital anomalies.
Abnormalities, Drug-Induced↗
Resistance to recombinant interferon alfa-2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies.
To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a.
Antibodies↗