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PubMed1982

Combination chemotherapy of advanced colorectal cancer utilizing 5-fluorouracil, semustine, dacarbazine, vincristine, and hydroxyurea: a phase III trial by the Eastern Cooperative Oncology Group (EST: 4275).

Patients who had measurable evidence of recurrent or metastatic colorectal carcinoma following surgery and radiotherapy but no prior chemotherapy were randomized to one of five combination chemotherapy programs. Four of the treatments utilized five consecutive days of fluorouracil (FU) (days 1--5 and days 36--40) plus one oral dose of semustine (ME) (day 1) every ten weeks: (A) FU + ME; (B) FU + ME + vincristine (VC) (day 1 and day 36); (C) FU + ME + dacarbazine (DC) (days 1, 2, 36, 37); (D) FU + ME + VC + DC. The fifth treatment option(E) used a weekly treatment program of FU I.V. on day 1 plus hydroxyurea (HU) P.O. on day 4. The overall response rate was 13% (60/472) and the median survival time from start of therapy for all patients was 31 weeks. The response rate and the median survival time for each combination was (A) 9/103 = 9%, 26 weeks; (B) 10/92 = 11%, 28 weeks; (C) 15/101 = 15%, 37 weeks; (D) 11/91 = 12%, 27 weeks; (E) 15/85 = 18%, 38 weeks. There is no statistical difference in response rate or survival duration among any of the treatment options. The therapies containing DC produced the only complete responses (3 patients on treatment C and 2 on D). Treatment D was also associated with the longest median response duration (Treatment D = 55 weeks). Treatment A (FU + ME) was associated with the highest incidence of life-threatening toxicity.

Antineoplastic Agents↗

PubMed1982

Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung.

Eight hundred sixty-five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow-up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes.

Carcinoma↗

PubMed1986

Treatment of polycythemia vera with hydroxyurea.

Thirty-six patients with polycythemia vera were treated with hydroxyurea for 12 to 67 months. Nineteen patients were previously treated with other drugs. In the vast majority of patients, an average dose of 1 g/day was sufficient to control hematocrit value and platelet count. Half of the patients experienced relief of pruritus, and two thirds experienced regression of splenomegaly. None of the patients had either thrombotic complications or leukemia. Four patients suffered from mild side effects, which included fever, hyperbilirubinemia, and stomatitis, and were relieved of their symptoms when treatment was stopped. However, two patients experienced renal failure, a possible major complication not described previously.

Aged↗

PubMed1986

Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea.

Seventeen patients with either chronic myelogenous leukemia (CML) or myelofibrosis with myeloid metaplasia (MMM) received 24 courses of splenic irradiation at this institution from 1973 to 1982. Eleven of the 17 patients had received prior chemotherapy. Patients were treated with 60Co gamma rays or 6 MV photons. The fraction size ranged from 15 to 100 rad and the total dose per treatment course from 15 to 650 rad, with the exception of one patient who received 1650 rad. Fourteen of 19 courses (71%) given for splenic pain yielded significant subjective relief while 17 of 26 courses given for splenomegaly obtained at least 50% regression of splenic size. Blood counts were carefully monitored before each treatment to limit hematologic toxicity. From this experience, the authors conclude that splenic irradiation effectively palliates splenic pain and reverses splenomegaly in the majority of patients with CML and MMM. Intermittent fractionation (twice or thrice weekly) is more convenient for the patient, appears to be as effective as daily treatment, and may be associated with less hematologic toxicity. Preliminary results of concurrent treatment with splenic irradiation and oral hydroxyurea show promise and warrant further study.

Adult↗

PubMed1987

Excretion of hydroxyurea into milk.

This article documents that hydroxyurea (HUR) is excreted into human breast milk, and it reviews the literature describing similar evaluations for other antineoplastic agents.

Adult↗

PubMed1990

5-Fluorouracil with oral leucovorin and hydroxyurea and concomitant radiotherapy for stage III non-small cell lung cancer.

Twenty-three patients with regionally advanced non-small cell lung cancer (NSCLC) (Stage III) were treated with continuous infusion 5-fluorouracil (5-FU) augmented by high-dose oral leucovorin and hydroxyurea and concomitant radiotherapy. This chemoradiotherapy regimen was administered during 5 days of every other week for six cycles (total radiation dose, 6000 cGy). Three patients (13%) had stable disease, 13 patients (57%) had a partial response (PR), and 1 patient (4%) had a complete response (CR). The overall response rate was 61% (95% confidence interval, 41% to 81%). At a median follow-up time of 19 months, the median survival time for all 23 patients was 12 months. The median time to disease progression was 6 months. Twelve patients have had disease progression outside of the chest, and only 3 patients have had intrathoracic disease progression as the site of first failure. The toxicities of this regimen consisted of mild to moderate myelosuppression and moderate degree dermatitis and mucositis. It was concluded that concomitant chemoradiotherapy with this regimen results in high local activity at acceptable toxicity. However, the systemic activity of this regimen was low, resulting in a high distant recurrence rate and a median survival time that was not different from that achieved with standard therapy. Therefore, its use, as defined in this study, cannot be recommended.

Administration, Oral↗

PubMed1990

Induction chemotherapy with a new regimen alternating cisplatin, fluorouracil with mitomycin, hydroxyurea and bleomycin in carcinomas of nasopharynx or other sites of the head and neck region.

Sixty-six patients with locally advanced (Stages III and IV) carcinoma of the head and neck were treated with three cycles of induction chemotherapy, consisting of cisplatin, fluorouracil (FU) infusion, bleomycin, mitomycin, and hydroxyurea, followed by radiotherapy and/or surgery. There were 48 men and 18 women with a median age of 55 years (range, 18 to 75 years) and Karnofsky performance status of 80 (range, 40 to 90). Primary site was nasopharynx (28 patients), followed by larynx (12) and others (26). Forty-one (62%) patients were presented with Stage IV disease. The response rate to induction chemotherapy was 27% complete response, 50% partial response, 20% stable disease, and 3% progressive disease. There was no significant difference in response rate between patients with cancer of nasopharynx or other sites (P greater than 0.1). Survival was 61% at 24 months. Patients with cancer of nasopharynx had a better survival than those with other primaries (P = 0.033). Toxicities from chemotherapy included alopecia (73%), nausea/vomiting (66%), leukopenia (54%), stomatitis (36%), anemia (32%), thrombocytopenia (16%), and diarrhea (9%). Grade IV toxicity was not observed. Induction chemotherapy with this new regimen resulted in a high response rate but may not be superior to cisplatin and FU alone. It can be safely combined with radiotherapy as a potentially curative therapy in squamous cell carcinoma of the head and neck. Chemotherapy followed by radiation therapy may yield survival similar to radical surgery in laryngeal and other head and neck cancers.

Adult↗

PubMed1991

Dual modulation of 5-fluorouracil using leucovorin and hydroxyurea. A phase I trial.

Oral hydroxyurea (HU) was added to a regimen of 5-fluorouracil (5-FU) plus leucovorin (LCV) administered as a continuous 24-hour infusion for 14 days. A previous report of the 5-FU plus LCV infusion established optimal dosages of 200 mg/m2/d and 5 mg/m2/d, respectively, for each agent. Oral HU was added to the regimen in total dosages of 0.5 g/d, 1.0 g/d, 1.5 g/d, or 2.0 g/d. Twenty-two patients received a total of 45 courses of treatment. Stomatitis was the dose-limiting side effect; it occurred in 3 of 14 courses with HU at 0.5 g/d (21%) and 9 of 17 courses with HU at 1.0 g/d (53%). Dosage escalation to 1.5 g/d or 2.0 g/d was possible in only 3 of 22 patients (17%). The median time to stomatitis was 10 days (range, 7 to 12 days). One response was observed in this heavily pretreated population. Phase II trials of HU plus LCV dual modulation of infusional 5-FU should use initial HU dosages of 0.5 g/d for the 14-day regimen described, with dose escalation as tolerated. Variable oral absorption presumably accounts for the small group of patients who can tolerate the higher doses of HU.

Administration, Oral↗

PubMed1995

Preclinical and clinical evaluation of 5-fluorouracil biochemical modulation with folinic acid and hydroxyurea for patients with colorectal carcinoma.

BACKGROUND: Approximately 140,000 new cases of colorectal carcinoma will be diagnosed in 1995 in the United States, and more than one-third of these patients will die from progressive disease. Despite the modest improvement in response rate with chemotherapy, little improvement in patient survival has been noted. Consequently, the evaluation of new agents, modalities, and combinations is needed. METHODS: Two cell lines, HCT 116 and COLO 320 HSR, were treated with various concentrations of 5-fluorouracil (5-FU), folinic acid (FA), and hydroxyurea (HU). Subsequently, 41 patients with advanced, measurable metastatic colorectal carcinoma were enrolled in the study. Patients were treated with oral doses of HU (500 mg) every 8 hours on Days 1 and 2, 5-FU (400-500 mg/m2) intravenously Day 2 and FA (100 mg/m2) intravenously on Day 2 of every week for 6 consecutive weeks, followed by a 2-week rest period. All patients were evaluable for toxicity, and 40 were evaluable for response. RESULTS: In both cell lines, the combination of 5-FU/FA/HU consistently produced the best cytotoxic effect. Clinically, the maximum tolerated dose of 5-FU was established at a level of 500 mg/m2 (450 mg/m2 for patients older than 70 years of age). Ten patients experienced Grade 3 or 4 toxicity, consisting mainly of diarrhea. Eleven of 40 evaluable patients responded (three complete responses, eight partial responses), with a median survival of 12+ months and time to progression of 8.5+ months. CONCLUSION: The biochemical modulation of 5-FU with FA and HU were significantly effective in treating patients with metastatic colorectal carcinoma. Overall, this regimen was well tolerated with only moderate toxicity. Further studies incorporating intravenous HU as well as a randomized Phase III study of 5-FU/FA/HU versus 5-FU/FA are recommended.

Antimetabolites, Antineoplastic↗

PubMed2001

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: amelioration by radical scavengers.

Hydroxyurea (HU) induces fetal hemoglobin (Hb F) production in patients with sickle cell anemia. The therapeutic dosage of HU used for Hb F induction often elicits myelosuppression, which becomes its major associated complication. We examined the effect of HU on hemoglobin modulation and the role of radical scavengers on these induced changes. In vitro exposure of human blood to various concentrations of HU at predetermined time intervals induced a progressive dose-dependent oxidation (MetHb formation) of both adult (Hb AA) and sickle (Hb SS) hemoglobins. The oxidative effect of HU on Hb SS was 3 times greater than its effect on Hb AA. Similar but less profound changes were observed in H2O2-treated samples. Hb F was, however, observed to be relatively resistant to HU-induced oxidative damage. A substantial protective effect of Hb by alpha-tocopherol, ascorbic acid, and D-mannitol was observed during pretreatment of Hb AA and Hb SS blood samples. Analyses of the hemoglobins and their globin chain components by high-performance liquid chromatography revealed a considerable protective effect by these free radical scavengers. These results indicate that the HU-induced damage of hemoglobin and their component globin chains can be reduced by radical scavengers.

Adolescent↗

PubMed1987

Biological time and the effects of hydroxyurea on DNA synthetic activity of bone marrow and tumor cells in mice bearing the Ehrlich ascites carcinoma.

The objective of this experiment was to attempt to induce, with hydroxyurea (HU), significant quantitative differences in the level of DNA-synthetic activity (DNA-SA) between a neoplastic cell population (the Ehrlich ascites carcinoma or EAC) and bone marrow in the same animal. Mice bearing a 5-day-old EAC were standardized to and kept on an LD 12:12 cycle (light 0600-1800 hr). They were treated with 500 mg/kg HU at 0500 hr (23 hr after lights on, or HALO) or at 1700 hr (11 HALO). DNA-SA was determined by liquid scintillation counting of 3H-thymidine incorporation into chemically isolated DNA. DNA-SA in bone marrow and EAC cells was monitored over the next 60 hr with subgroups of ten mice each killed every 3 hr beginning 3 hr after treatment with HU. The circadian system of the host influenced the response of the bone marrow to HU; i.e., the response to HU administered at 0500 hr was different both qualitatively and quantitatively from that for HU given at 1700 hr. Comparisons of DNA-SA in bone marrow and EAC from the same animal revealed time points after treatment with HU when DNA-SA in the EAC was high, but DNA-SA in bone marrow was low. These differences in the level of DNA-SA between a tumor cell population and bone marrow should be of therapeutic value; i.e., executor doses of anti-DNA-SA drugs such as cytosine arabinoside could be given at that point in time after treatment with HU when DNA-SA in the tumor was high, but DNA-SA in the bone marrow was low.

Animals↗

PubMed2002

Hydroxyurea (HU) for prevention of recurrent stroke in sickle cell anemia (SCA).

Cerebrovascular accident (CVA) is a major cause of morbidity and death in sickle cell anemia (SCA). Transfusion of packed erythrocytes is widely used to prevent this complication. However, chronic transfusion may lead to iron overload, alloimmunization, or infections. Cost and compliance may compromise transfusion therapy. A possible alternative, the prophylactic use of hydroxyurea (HU), has not been tried to determine whether it may prevent recurrent stroke. We used HU in five children with SCA who had suffered stroke, in three of them after a first episode and in the other two after a second CVA. Four had infarctive stroke and one a transient ischemic attack (TIA). Four patients took HU at a dose of 40 mg/kg/d, one patient at 30 mg/kg/d. None of the patients had recurrent stroke during 42-112 months of observation. None experienced pain crises. In all, HbF increased significantly and was maintained above 14.7% during treatment. The total Hb concentration increased 19.5 g/L (median) above the value before treatment. HU was well tolerated. None of the five children had leukopenia or thrombocytopenia during therapy. HU appears to prevent recurrence of stroke in SCA without risk of major toxicity.

Adolescent↗

PubMed2003

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease.

Fetal hemoglobin (HbF) level and the HbF responses to hydroxyurea (HU) vary among patients with sickle cell disease and are, at least in part, genetically regulated. We hypothesized that siblings with sickle cell disease are likely to share the same parental beta-like globin gene clusters with their cis-acting regulatory sequences and therefore, if regulation of this response is linked to the beta-globin gene cluster, might have concordant HbF responses to HU. Accordingly, we studied 26 families (30 sib pairings), 20 with sickle cell anemia (three families had three siblings) and 6 families with HbS-beta-thalassemia (one family had three siblings, and one family consisted of monozygotic twins), to see if siblings with sickle cell disease had discordant or concordant changes in HbF during HU treatment. Intraclass correlation coefficients (r) showed a high, positive correlation between sibs for HbF levels before and during HU treatment and a concordant change in HbF response from baseline to treatment-associated levels. Changes in mean corpuscular volume (MCV) paralleled HbF levels, while the expected correlations between treatment-associated fall in leukocyte count and increase in MCV were also present. Our results provide additional evidence that some elements that regulate HbF expression are linked to the beta-globin gene cluster.

Adolescent↗

PubMed2004

Hydroxyurea-induced hemolytic anemia in a patient with essential thrombocythemia.

Hydroxyurea (HU) has been used in patients with essential thrombocythemia (ET) to reduce the frequency and severity of thrombotic complications of the disease. It acts by causing bone marrow depression, resulting in a decrease in platelet and leukocyte counts and in anemia with megaloblastosis. Herein we report a case of an 80-year-old man with ET who developed severe hemolytic anemia requiring multiple packed RBC transfusions while being treated with HU. The hemolysis persisted until discontinuation of the drug. This case suggests hemolysis as a potential side effect of HU and raises the clinical concern that not all HU-induced anemia is secondary to erythropoiesis depression. With the increasing use of HU in the management of ET, hemoglobinopathy, and other diseases, the importance of monitoring for hemolysis must be further emphasized in these patients.

Aged↗

PubMed2005

Effects of hydroxyurea in a population of Brazilian patients with sickle cell anemia.

Fetal hemoglobin (HbF) inhibits the polymerization of sickle hemoglobin, modulating the clinical features of sickle cell anemia (SCA). Hydroxyurea (HU) therapy can increase the HbF level, although its production can be influenced by genetic determinants. Twenty-two Brazilian SCA patients were evaluated over 5 years before and after HU use. We analyzed (1) betaS haplotype; (2) patient characteristics; and (3) toxicity. No differences between age, sex, and HU response were observed. We found 40.9% of homozygous for Bantu haplotype, and, in contrasting to other trials, we observed HbF level increase in this group (3.84-9.08 g/dL, P=0.003). Adverse effects were rare. Labyrinthitis was observed in 2 (9.10%) patients after HU use, although this complication had not been described before.

Adolescent↗

PubMed2005

Hydroxyurea therapy for sickle cell disease in community-based practices: a survey of Florida and North Carolina hematologists/oncologists.

Little is known about patterns of hydroxyurea (HU) use by community-based hematologist/oncologists (H/Os) for the treatment of sickle cell disease (SCD). Determination of these practice patterns pertaining to adult SCD patients was the focus of this study. A self-administered survey was mailed to H/Os in two southeastern states. Replies were received from 70% of eligible physicians. This study focuses on responses from 184 community H/Os and a comparison group of 30 university-based/affiliated H/Os providing ongoing care for at least 3 SCD patients/month. The majority of community H/O respondents saw less than 3 SCD patients/month. HU was prescribed by more than half (55%) of community H/Os in at least 10% of their patients. The most common reasons cited for prescribing HU include frequent painful crises (76%), chronic pain with frequent narcotic use (58%), and acute chest syndrome (43%). Although the majority of community H/Os care for few patients with SCD, the reported indications for HU were consistent with currently accepted recommendations. However, community H/Os reported acute chest syndrome, stroke, and pulmonary hypertension as indications for HU less often than the academic H/O group. Barriers to wider use of HU include physician concerns about carcinogenic potential, doubts about HU effectiveness, perceived patient apprehension about adverse effects, concern about lack of contraceptive use, and patient compliance. Further resources should focus on updating physicians on recently published material supporting the effectiveness of HU in symptomatic SCD as well as providing management guidelines to optimize the use of HU.

Anemia, Sickle Cell↗

PubMed1989

Effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo.

We have monitored the rheological effects of hydroxyurea (HU) on erythrocytes obtained from two patients with severe sickle cell anemia who were enrolled in a therapeutic trial of this drug. Erythrocyte membrane stability and whole cell and membrane deformability of red cells from treated and untreated patients and normal controls were determined in room air using an ektacytometer--a laser viscodiffractometer. The percentage of dense cells was quantitated by centrifugation on a discontinuous Stractan density gradient. F reticulocytes (FR), absolute F reticulocytes (AFR), and F cells (FC) were determined by single-cell radial immunolgic assays. After 1 year of treatment with HU, there was a significant increase in the level of hemoglobin (Hb) F, FR, AFR, and FC. The degree of anemia remained the same, but there was significant increase in the mean cell volume (MCV) and a significant decrease in the mean corpuscular Hb concentration (MCHC). Whole cell deformability improved by twofold, but membrane stability remained within normal limits. The hydration status of sickle erythrocytes improved as was indicated by a change toward normal in gradient osmotic ektacytometry, an increase in RBC K+ content, a decrease in percent of dense cells, and a decrease in the MCHC. The data indicate that, in addition to its effect on the production of Hb, F, HU has a salutary effect on whole cell deformability and on the hydration status of sickle erythrocytes. Determination of the rheological properties of erythrocytes may be of value in monitoring the response to HU.

Anemia, Sickle Cell↗

PubMed1981

Circadian rhythm in mitotic index of corneal epithelium: presence of Ehrlich ascites carcinoma and treatment with saline or hydroxyurea.

A study of the circadian rhythm in the mitotic index (MI) of the corneal epithelium was completed in non-tumor-bearing mice and in mice bearing the Ehrlich ascites carcinoma (EAC). All mice were standardized to a light-dark cycle with 12 hours of light from 0600 to 1800 CST alternating with 12 hours of darkness from 1800 to 0600 CST. Treatments included injection with saline (SAL) or hydroxyurea (HU) at different circadian times. This investigation demonstrated that: (1) Data from untouched animals cannot serve as proper controls because treatment with SAL altered the level of the MI, but only during the diurnal, not the nocturnal, phase of the circadian cycle; (2) the presence of the EAC depressed the level of the MI, but this inhibition was only detected during the diurnal period; (3) treatment with 500 mg/kg HU injected at 0500 caused more perturbation in this rhythm than did treatment with 500 mg/kg HU at 1700; (4) when 500 mg/kg HU was given at 2000 and 0100 and 0500, the perturbation of the rhythm was greater than when 500 mg/kg HU was given at 0900 and 1400 and 1700; (5) when 3000 mg/kg HU was given at 1700 and compared to 500 mg/kg HU at 1700, little difference in the overall circadian profiles of these rhythms was observed, indicating that the circadian control mechanisms operating on the MI exerted a greater influence than did a dosage change from 500 to 3000 mg/kg HU; and (6) a comparison of the practice of plotting experimental and control data as "hours after treatment" versus using a "time of day" plot for the same data demonstrated that the "hours after treatment" plot is very misleading because it fails to account for the significant circadian oscillation in this in vivo system.

Animals↗