Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I).

BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS AND METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.

Conversion from cytomegalovirus universal prophylaxis with valganciclovir to the preemptive monitoring approach to manage leukopenia after kidney or pancreas transplantation.

PURPOSE: In clinical practice, conversion from universal cytomegalovirus prophylaxis (CMV PPX) with valganciclovir (VGC) to targeted therapy (preemptive monitoring, PEM) is often pursued in the setting of leukopenia. It is unknown if this is an effective strategy. METHODS: Adult patients receiving a kidney and/or pancreas transplant were included if converted from PPX to PEM between 9/1/19 and 3/1/20 due to leukopenia. A positive CMV viral load (VL) was defined as CMV PCR greater than the lower limit of quantification (LLOQ) based on local lab testing. A CMV VL of >500 IU/mL was chosen as the preemptive treatment (PET) threshold. Primary objective was to describe the impact of conversion on resolution of leukopenia. Secondary objectives were to assess PEM associated outcomes. RESULTS: There were 49 patients converted from PPX to PEM due to leukopenia in the study period; 88% were KTRs and 96% received lymphocyte-depleting induction; 84% were seropositive at transplant (R+) and 16% were high-risk (D+/R-). Mean WBC at time of enrollment was 1.4 ± 0.4. After PEM conversion, WBC recovered to >3 in 87.8% of the population in a mean of 26.8 ± 24.5 days. Immunosuppression was modified in 96% of the population and GCSF was required in 46.9% of patients. CMV viremia occurred in 36.7% of the population; 78% were KTRs and 94% were R+. Time from PEM enrollment to PET was 64 ± 34 days. Median VL at first detection was 587 IU/mL, median peak was 1920 IU/mL. Five patients (27.8%) presented with symptoms consistent with CMV syndrome, none had end organ disease. Six patients (33%) presented with a VL <500 IU/mL at first detection, but all subsequently surpassed the threshold and required PET. Mean duration of PET was 25 ± 11 days. Mean change in WBC in response to PET was -0.4 ± 1.3. Immunosuppression required further adjustment in 61% of patients. There were no deaths or graft loss due to CMV at last follow-up. CONCLUSION: In kidney and pancreas transplant recipients who undergo PEM conversion due to leukopenia, withholding of VGC can improve leukopenia, but other concomitant measures are necessary. This population should be considered fairly high risk, with a threshold of treatment of first quantifiable replication. Our findings suggest lack of harm from this approach but highlight the importance of close monitoring to prevent symptomatic replication. Larger studies with longer follow-up are needed to better evaluate the impact of PEM conversion on late-onset CMV and patient and graft outcomes.

Cabazitaxel schedules in metastatic castration-resistant prostate cancer: a review.

Cabazitaxel (25 mg/m2 every 3 weeks) is the standard second-line chemotherapy for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. It is associated with a risk of neutropenic complications, which may be a barrier to its use in daily clinical practice, particularly in frail elderly patients. Here the authors reviewed key studies conducted with cabazitaxel (TROPIC, PROSELICA, AFFINITY, CARD and the European compassionate use program) and pilot studies with adapted schedules. Based on this review, the use of prophylactic granulocyte colony-stimulating factor from cycle 1 appears crucial to maximize the benefit-risk ratio of cabazitaxel in metastatic castration-resistant prostate cancer. Preliminary data with alternative schedules look promising, especially for frail patients. Results of the ongoing Phase III CABASTY trial (ClinicalTrials.gov: NCT02961257) are awaited.

The potential agents from food for preventing leukopenia induced by benzene: garlic preparations.

Leukopenia is the early clinical manifestation of benzene poisoning. The aim of our research was to evaluate the preventive effects of three kinds of garlic preparations on benzene induced leukopenia. The mouse model of Leukopenia was established with benzene orally. At the same time, mice were administrated with garlic homogenate (GH), garlic oil (GO) or diallyl trisulfide (DATS) as preventional measures. The counts of white blood cells (WBC), the organ indexes, pathological examinations, blood biochemical parameters, weight gains, and food intakes were evaluated to observe the protective effect and potential adverse events. The results demonstrated that the counts of WBC increased by 144.04%, 140.07%, and 148.34%, respectively, after intervention by GH (400 mg/kg), GO (60 mg/kg) and DATS (30 mg/kg), compared with that in the model group. The spleen and thymus indexes in the benzene model group were 44.99% and 54.04% lower than those in the blank control group, the number of spleen nodules reduced and the thymus atrophy, which were restored by three garlic preparations at different degree. The results suggested that the three preparations all could prevent the leukopenia and protect the organ injuries induced by benzene. However, the spleen index and weight gains revealed that GH and GO brought more adverse events than DATS.

Using PARP Inhibitors in Advanced Ovarian Cancer.

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease.

BACKGROUND & AIMS: More than 20% of patients with inflammatory bowel disease (IBD) discontinue thiopurine therapy because of severe adverse drug reactions (ADRs); leukopenia is one of the most serious ADRs. Variants in the gene encoding thiopurine S-methyltransferase (TPMT) alter its enzymatic activity, resulting in higher levels of thiopurine metabolites, which can cause leukopenia. We performed a prospective study to determine whether genotype analysis of TPMT before thiopurine treatment, and dose selection based on the results, affects the outcomes of patients with IBD. METHODS: In a study performed at 30 Dutch hospitals, patients were assigned randomly to groups that received standard treatment (control) or pretreatment screening (intervention) for 3 common variants of TPMT (TPMT*2, TPMT*3A, and TPMT*3C). Patients in the intervention group found to be heterozygous carriers of a variant received 50% of the standard dose of thiopurine (azathioprine or 6-mercaptopurine), and patients homozygous for a variant received 0%-10% of the standard dose. We compared, in an intention-to-treat analysis, outcomes of the intervention (n = 405) and control groups (n = 378) after 20 weeks of treatment. Primary outcomes were the occurrence of hematologic ADRs (leukocyte count < 3.0*10(9)/L or reduced platelet count < 100*10(9)/L) and disease activity (based on the Harvey-Bradshaw Index for Crohn's disease [n = 356] or the partial Mayo score for ulcerative colitis [n = 253]). RESULTS: Similar proportions of patients in the intervention and control groups developed a hematologic ADR (7.4% vs 7.9%; relative risk, 0.93; 95% confidence interval, 0.57-1.52) in the 20 weeks of follow-up evaluation; the groups also had similar mean levels of disease activity (P = .18 for Crohn's disease and P = .14 for ulcerative colitis). However, a significantly smaller proportion of carriers of the TPMT variants in the intervention group (2.6%) developed hematologic ADRs compared with patients in the control group (22.9%) (relative risk, 0.11; 95% confidence interval, 0.01-0.85). CONCLUSIONS: Screening for variants in TPMT did not reduce the proportions of patients with hematologic ADRs during thiopurine treatment for IBD. However, there was a 10-fold reduction in hematologic ADRs among variant carriers who were identified and received a dose reduction, compared with variant carriers who did not, without differences in treatment efficacy. ClinicalTrials.gov number: NCT00521950.

Seminiferous epithelium damage after short period of busulphan treatment in adult rats and vitamin B12 efficacy in the recovery of spermatogonial germ cells.

Several different strategies have been adopted in attempt to recover from chemotherapy-damaged spermatogenesis that is often seen in oncologic patients. In this study, we have evaluated the impact of short period of exposure to busulphan on the haemogram and seminiferous epithelium of adult rats, focusing on spermatogonial depletion and Sertoli cell (SC) integrity. We then examined whether vitamin B12 supplementation improves the haematological parameters and spermatogonia number. The animals received 10 mg/kg of busulphan (BuG) or busulfan+vitamin B12 (Bu/B12 G) on the first and fourth days of treatment. In H.E.-stained testicular sections, the areas of the seminiferous tubule (ST) and seminiferous epithelium were measured. The number of spermatogonia in H.E-stained and PCNA-immunolabelled testicular sections was quantified. The frequency of tubules with abnormal SC nuclei or TUNEL-positive SC was evaluated. Vimentin immunofluorescence in ST was also evaluated. In BuG and Bu/B12 G, the animals showed leukopenia and thrombocytopenia, but the body weight reduced only in BuG. The areas of ST and seminiferous epithelium decreased in Bu/B12 G and BuG. In BuG, the number of H.E.-stained and PCNA-immunolabelled spermatogonia reduced significantly. The frequency of tubules containing abnormal SC nuclei and TUNEL-positive SC increased and the vimentin immunoexpression pattern changed. In Bu/B12 G, the number of H.E.-stained or PCNA-immunolabelled spermatogonia increased fourfold in comparison with BuG. The structural changes in ST after 6 days of busulphan exposure may be associated with the potential effect of this anti-neoplastic agent on SC. The increased number of spermatogonia in the busulphan-treated animals receiving vitamin B12 indicates that this vitamin can be an adjuvant therapy to improve the fertility in male cancer patients.

The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis severity and reverts leukopenia induced by Irinotecan.

Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1ß production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1ß production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment.

Measurement of red blood cell 6-thioguanine nucleotide is beneficial in azathioprine maintenance therapy of Chinese Crohn's disease patients.

OBJECTIVE: It remains controversial whether 6-thioguanine nucleotide (6-TGN)-based dose adjusting can be beneficial in azathioprine (AZA) therapy. This study is designed to assess the role of 6-TGN concentrations in maintaining clinical remission in Chinese patients with Crohn's disease (CD). MATERIAL AND METHOD: We performed a prospective observational study and collected data of CD patients in the First Affiliated Hospital of Anhui Medical University from June 2013 to April 2014. Demographic material, CD activity index, 6-TGN concentration, and laboratory tests were recorded at baseline and at each visit. In addition, 6-TGN was measured when drug adverse effects occurred. All patients achieved maintenance stage were administered a stable AZA dose at least 3 months before enrollment and were followed up at least 12 months. Thiopurine S-methyltransferase (TPMT) genotype was measured before AZA treatment. RESULTS: Sixty-nine patients receiving maintenance therapy were analyzed. A positive correlation was found between 6-TGN levels and AZA dose (r = 0.258, p = 0.032). The mean 6-TGN concentration was 302.06 ± 115.84 in the remission group vs. 264.94 ± 164.53 pmol/8 × 10(8) RBC in those with active disease (t = 0.847, p = 0.40), and 197.74 ± 66.54 pmol/8 × 10(8) RBC in patients who relapsed vs. 310.26 ± 122.38 pmol/8 × 10(8) RBC for those in sustained remission (t= -2.541, p = 0.013). In the leukopenia group, the 6-TGN concentration was 469.11 ± 115.53 pmol/8 × 10(8) RBC vs. 257.31 ± 83.74 pmol/8 × 10(8) RBC in the non-leukopenia group (t = 7.622, p < 0.001). There was a significant negative correlation between leukocyte count and 6-TGN concentration (r= -0.326, p = 0.006). CONCLUSIONS: 6-TGN measurement is a helpful method of preventing disease relapse and avoiding leukopenia in individual azathioprine maintenance therapy.

Feasibility evaluation of hypofractionated radiotherapy with concurrent temozolomide in elderly patients with glioblastoma.

BACKGROUND: Although hypofractionated radiotherapy (HFRT) is preferred to conventionally fractionated radiotherapy when treating elderly patients with glioblastoma, the benefits and tolerability of HFRT with concurrent temozolomide (TMZ) remain unknown for such patients. We assessed the feasibility and outcomes of elderly patients with glioblastoma treated with HFRT and concurrent TMZ. METHODS: We retrospectively reviewed the medical records of 11 patients aged ≥70 years who were treated with HFRT and concurrent TMZ. All patients had newly diagnosed and histologically confirmed glioblastoma and were treated at our institution between October 2011 and April 2015. The median age was 74 years (range, 70-85 years). Total resection/subtotal resection/biopsy were performed in 2/5/4 patients, respectively. The planning target volume included the T1-enhancing tumor and the resection cavity plus 2-cm margins, and all surrounding edema. The median prescription dose was 35 Gy (range, 35-42.5 Gy), delivered in 10 fractions. Seven patients received TMZ at 150 mg/m2 for 5 days and 4 received TMZ at 75 mg/m2 during HFRT. Overall survival (OS) was defined as the time from surgery to death or the last follow-up. RESULTS: The median follow-up period was 13.2 months. The median OS and progression-free survival (PFS) times were 13.2 and 7.0 months, respectively. One patient experienced grade 4 neutropenia, lymphocytopenia, and thrombocytopenia. No grade 3 or higher nonhematological adverse event was noted. CONCLUSION: Our analysis demonstrated the feasibility of HFRT with concurrent TMZ used to treat elderly patients with glioblastoma. Further prospective clinical trials are needed to define therapies that balance efficacy with tolerability.

[Clinical Efficacy of Cepharanthin(R)for Radiotherapy-Induced Leukopenia - A Nationwide, Multicenter, and Observational Study].

The clinical efficacy and safety of cepharanthin for the treatment of radiotherapy-induced leukopenia were reevaluated at multiple institutions.Clinical data of cancer patients aged over 20 years old, who received a total radiotherapy dose above 40 Gy, and who were treated with cepharanthin for more than 2 weeks between April 2007 and November 2012, were evaluated. Data from 65 patients(males: 31, females: 34)from 7 facilities were analyzed to assess efficacy and adverse events.The mean leukocyte count was significantly higher at the end of the treatment compared with the initial data.However, no significant differences were observed in erythrocyte and platelet counts.No adverse events attributed to cepharanthin were reported.Although this was a retrospective study, cepharanthin was found to be safe and significantly effective for the management of leukopenia caused by radiotherapy.

[Intradermal needling and acupuncture in prevention and treatment of leukopenia after chemotherapy with spleen-kidney deficiency: a randomized controlled trial].

OBJECTIVE: To compare the clinical effect of intradermal needling and acupuncture in prevention and treatment of leukopenia after chemotherapy with spleen-kidney deficiency. METHODS: A total of 90 patients with malignant tumor who received chemotherapy were randomly divided into a intradermal needling group (30 cases, 1 case dropped out), an acupuncture group (30 cases, 2 cases dropped out, 1 case was eliminated) and a control group (30 cases). The control group received conventional symptomatic treatment after chemotherapy. On the basis of the treatment in the control group, the intradermal needling group received intradermal needling at Guanyuan (CV 4), Dazhui (GV 14) and bilateral Geshu (BL 17), Zusanli (ST 36)，Shenshu (BL 23), the needles were retained for 48 h, once every other day. On the basis of the treatment in the control group, the acupuncture group received conventional acupuncture at the same acupoints as the intradermal needling group, once every other day. The treatment started from the first day of chemotherapy, for a total of 2 weeks in the three groups. The white blood cell count, neutrophil count, hemoglobin content, platelet count and Karnofsky performance status (KPS) score before treatment and on 3rd, 7th, 14th, and 21st days after treatment were compared among the three groups. The incidence and grading of leukopenia and the usage of leukocyte-boosting drug during chemotherapy cycle was recorded. RESULTS: On 7th day after treatment, the white blood cell count in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01, P<0.05). On the 14th day after treatment, the hemoglobin content in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01). On the 7th, 14th, and 21st days after treatment, the platelet count in the acupuncture group was higher than that in the control group (P<0.01), on the 14th and 21st days after treatment, the platelet count in the intradermal needling group was higher than that in the control group (P<0.01). There was no statistically significant difference among the three groups after treatment in terms of neutrophil count, KPS score, incidence and grading of leukopenia, and the usage of leukocyte-boosting drug (P>0.05). CONCLUSION: Both intradermal needling and acupuncture can effectively increase peripheral blood white blood cell count, hemoglobin content and platelet count during chemotherapy cycle, reduce the toxicity of chemotherapy drug to bone marrow hematopoietic function, and alleviate bone marrow suppression after chemotherapy. The two treatments are equally effective.

[Modification of hematosupressive action of ionizing radiation by dicarbamine].

There was studied the effect of different doses of Dicarbamine by means of oral medical-prophylactic and medical administration on the peripheral blood of rabbits in conditions of experimental radiation damage to the blood system. The drug provided the safety of circulating red blood cells at rather high level, prevented the development of severe post-radiation thrombocytopenia, reduced post-radiation leukocytopenia, accelerated processes of recovery of peripheral blood leukocytes to the initial level by segmented neutrophils and lymphocytes.

[Comparative study of the hemato-protective effect of Dicarbamine and Leykostime in experimental radiation damage to the blood system].

There was studied the influence Dicarbamine and Leykostime on peripheral blood leukocyte composition of rabbits in experimental radiogenic damage to the blood system. Dicarbamine significantly insured the safety of circulating red blood cells, prevented the development of severe postradiation thrombocytopenia, reduced postradiation leukocytopenia, and accelerated the recovery of peripheral blood leukocytes to the initial level by segmented neutrophils and lymphocytes. Leukostime ensured the safety of peripheral blood leukocytes however was less effective than Dicarbamine to prevent postradiation deficit of circulating red blood cells and thrombocytes.

Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects.

Prospective studies have indicated an age-related impairment of the immune response. Carotenoids have been hypothesised to enhance immune cell function. The aim of the present study was to describe the age-related effects and the impact of in vivo dietary carotenoid depletion and repletion on specific and non-specific immunity. A total of ninety-eight healthy male subjects (aged 20-75 years) received a carotenoid-depleted diet for 3 weeks and were then supplemented daily for 5 weeks with 30 mg ß-carotene, 15 mg lycopene and 9 mg lutein. Blood samples were collected at study entry, after depletion and supplementation, and biomarkers of immune status were determined. We found that serum IgA levels were positively correlated with ageing. Lymphocyte phenotyping indicated an increase with age in the memory T-helper cell subpopulation (CD4⁺CD45RO⁺) concomitantly with a decrease in naive T-helper cells (CD4⁺CD45RA⁺). A significant increase in the natural killer cells subpopulation and a small decrease in B lymphocytes were also observed, especially for the oldest volunteers. From ex vivo cell function exploration, a positive correlation was observed between age and IL-2 production of phytohaemagglutinin-stimulated lymphocytes. Neutrophils' bactericidal activity was significantly impaired with age (from 50 years) and was modulated by carotenoid status. An age effect was found on neutrophils' spontaneous migration but not on directed migration. Immune response in healthy human subjects is mostly affected by age rather than by dietary carotenoid depletion and repletion. Even in carefully selected healthy volunteers, some age-related immune changes occur predominantly from 50 years onwards. This immunosenescence could generate a loss in the immune system adjustment capacity.

Effects of a Chinese medical herbs complex on cellular immunity and toxicity-related conditions of breast cancer patients.

Rose geranium (Pelargonium graveolens, Geraniaceae) has anti-cancer and anti-inflammatory properties, and promotes wound healing. Similarly, Ganoderma tsugae (Ganodermataceae), Codonopsis pilosula (Campanulaceae) and Angelica sinensis (Apiaceae) are traditional Chinese herbs associated with immunomodulatory functions. In the present study, a randomised, double-blind, placebo-controlled study was conducted to examine whether the Chinese medicinal herb complex, RG-CMH, which represents a mixture of rose geranium and extracts of G. tsugae, C. pilosula and A. sinensis, can improve the immune cell count of cancer patients receiving chemotherapy and/or radiotherapy to prevent leucopenia and immune impairment that usually occurs during cancer therapy. A total of fifty-eight breast cancer patients who received chemotherapy or radiotherapy were enrolled. Immune cell levels in patient serum were determined before, and following, 6 weeks of cancer treatment for patients receiving either an RG-CMH or a placebo. Administration of RG-CMH was associated with a significant reduction in levels of leucocytes from 31·5 % for the placebo group to 13·4 % for the RG-CMH group. Similarly, levels of neutrophils significantly decreased from 35·6 % for the placebo group to 11·0 % for the RG-CMH group. RG-CMH intervention was also associated with a decrease in levels of T cells, helper T cells, cytotoxic T cells and natural killer cells compared with the placebo group. However, these differences between the two groups were not statistically significant. In conclusion, administration of RG-CMH to patients receiving chemotherapy/radiotherapy may have the capacity to delay, or ease, the reduction in levels of leucocytes and neutrophils that are experienced by patients during cancer treatment.

Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia.

BACKGROUND: To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS: Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS: Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 × 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS: Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential.

Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1.

UNLABELLED: The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer. PATIENTS AND METHODS: After a first standard dosed FEC course (5-fluorouracil 600 mg/m(2), epirubicin 60 mg/mg(2) and cyclophosphamide 600 mg/m(2)), patients who did not reach leukopenia grade III or IV were randomised to standard doses (group standard) or doses tailored to achieve grade III leukopenia (group tailored) at courses 2-7. Patients who achieved leukopenia grade III or more after the first course were not randomised but continued on standard doses (group registered). RESULTS: Both planned and actually delivered number of courses (seven) were the same in all three arms. The relative dose intensity was increased by a factor of 1.31 (E 1.22, C 1.43) for patients in the tailored arm compared to the expected on standard dose. Ninety percent of the patients in the tailored arm achieved leukopenia grade III-IV compared with 29% among patients randomised to standard dosed therapy. Dose tailoring was associated with acceptable acute non-haematological toxicity with more total alopecia, nausea, vomiting and fatigue. CONCLUSION: Dose tailoring according to leukopenia was feasible. It led to an increased dose intensity and was associated with acceptable excess of acute non-haematological toxicity.

Comparison of pegfilgrastim on day 2 vs. day 4 as primary prophylaxis of intense dose-dense chemotherapy in patients with node-positive primary breast cancer within the prospective, multi-center GAIN study: (GBG 33).

BACKGROUND: Preliminary data suggest that pegfilgrastim given on day 4 (P4) might be superior to pegfilgrastim on day 2 (P2) in reducing grade 4 leucopenia. METHODS: Patients with node-positive primary breast cancer receiving epirubicin-paclitaxel-cyclophosphamide chemotherapy were randomized to receive P2 versus P4. Primary endpoint was leucopenia grade 4, assuming a risk reduction of 50% with P4 from 50% in P2 to 25% with P4. RESULTS: Three-hundred fifty-one patients were randomized to P2 (n = 174) versus P4 (n = 177). The rate of leucopenia (grade 4) was 47.1% with P2 and 42.0% with P4 (p = 0.387), neutropenia (grade 3 + 4) was 47.9% versus 40.8% (p = 0.337), FN was 4.7% versus 8.0% (p = 0.271), and infections was 29.9% versus 25.4% (p = 0.404), respectively. CONCLUSION: This study failed to demonstrate that pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections.