Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center.

BACKGROUND: FLAG ± Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), is a salvage chemotherapy regimen for relapsed or refractory (R/R) acute myeloid leukemia (AML), with complete remission (CR) rates historically ranging from 52% to 63%. We review the outcomes for patients with R/R AML treated with FLAG ± Ida at the University of California Davis Comprehensive Cancer Center. PATIENTS AND METHODS: Adult patients (≥ 18 years) with R/R AML who received FLAG or FLAG + Ida from January 1, 2012 to October 31, 2016 were identified via chart review. Outcomes evaluated were CR, CR with incomplete hematologic recovery (CRi), overall response rate, overall survival (OS), relapse-free survival, and adverse events. RESULTS: Forty-two patients were included. The median age was 52 years (range, 23-73 years), and 57% were male. Sixteen (38.1%) patients had relapsed disease, and 26 (61.9%) had refractory disease. Most (n = 35; 83.3%) patients had European LeukemiaNet intermediate-risk AML. Responses were CR in 20 (47.6%) and CRi in 6 (14.3%). The median OS was 10 months (range, 0.8-51 months), and the median relapse-free survival was 12 months (range, 1-51 months) for responders. The median OS for patients who achieved CR was not reached, and the estimated 48-month survival rate was 56%. The median OS after CRi or no response was 3.47 and 2.17 months, respectively. The median OS was not significantly different when censored for stem cell transplant following chemotherapy, nor with use/deferral of idarubicin. The most common adverse effects were pancytopenia and infection. CONCLUSION: Patient outcomes after treatment with FLAG ± Ida for R/R AML remain similar to prior reports, confirming its role as a salvage regimen for these patients.

Phase 1 study of combinatorial sorafenib, G-CSF, and plerixafor treatment in relapsed/refractory, FLT3-ITD-mutated acute myelogenous leukemia patients.

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.

Granulocyte Colony-Stimulating Factor (G-CSF) for the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) is a common medical condition with a poor prognosis for recovery and catastrophic effects on a patient's quality of life. Available treatments for SCI are limited, and the evidence suggesting their harmful side effects is more consistent than any suggestion of clinical benefit. Developing novel safe and effective therapeutic options for SCI is crucial. Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine with known multifaceted effects on the central nervous system. Herein, we review the accumulating preclinical evidence for the beneficial effects of G-CSF on functional and structural outcomes after SCI. Meanwhile we present and discuss multiple mechanisms for G-CSF's neuroprotective and neuroregenerative actions through the results of these studies. In addition, we present the available clinical evidence indicating the efficacy and safety of G-CSF administration for the treatment of acute and chronic traumatic SCI, compression myelopathy, and SCI-associated neuropathic pain. Our review indicates that although the quality of clinical evidence regarding the use of G-CSF in SCI is inadequate, the encouraging available preclinical and clinical data warrant its further clinical development, and bring new hope to the longstanding challenge that is treatment of SCI.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Prophylactic long-acting granulocyte-colony stimulating factors (G-CSF) in gynecologic malignancies: an oncologic expert statement.

We reviewed the status of the use of the prophylactic long-acting granulocyte colony-stimulating factors (G-CSFs) pegfilgrastim and lipegfilgrastim in gynecologic malignancies. Long-acting G-CSFs should not be used in weekly regimens. Filgrastim is not indicated in patients with febrile and/or severe neutropenia after administration of long-acting G-CSF in the same cycle. One study has shown a moderate effect on febrile neutropenia of ciprofloxacin when co-administered with pegfilgrastim. There is broad evidence from meta-analyses that pegfilgrastim effectively reduces severe neutropenia. In parallel, its adverse effects have been studied extensively. All-cause mortality was significantly reduced by pegfilgrastim. The glycopegylated long-acting G-CSF, lipegfilgrastim has demonstrated antineutropenic efficacy similar to that of pegfilgrastimin in one breast cancer study. In another pivitol non-small cell lung cancer study, impaired survival was observed in the lipegfilgrastim group during the first 30 days of study. The European Medicines Agency claimed more profound safety data to be provided for lipegfilgrastim by 2017.

Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

Combination of autologous transplantation of G-CSF-mobilized peripheral blood mononuclear cells and Panax notoginseng saponins in the treatment of unreconstructable critical limb ischemia.

BACKGROUND: The aim of this study is to explore the efficacy and safety of the combination of autologous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMNCs) and Panax notoginseng saponins (PNS) in the treatment of unreconstructable critical limb ischemia (CLI). METHODS: We performed an open-label, parallel-group, single-center, randomized clinical trial in this study. A total of 52 patients were enrolled and randomly divided into 2 groups (the PBMNC + PNS group and the PBMNC group) in a 1:1 ratio. Evaluation variables, including changes in the ankle-brachial index (ABI) of ischemic limbs, ulcer area, severity of rest pain, transcutaneous oxygen pressure (T(C)PO2), and 6-min walk distance from baseline to week 8 and 16, as well as angiographic scores for new collateral vessel formation at week 16, were used to compare the benefits of these 2 treatment approaches. RESULTS: After 16 weeks of treatment, improvement in ABI, T(C)PO2, and 6-min walk distance was significantly better in the PBMNC + PNS group. In addition, the combination of PBMNC transplantation and PNS administration yielded a greater reduction in ulcer area and severity of rest pain than did PBMNC transplantation alone. The proportion of patients experiencing any adverse event was similar between both treatment groups. Adverse events caused by PBMNC transplantation or PNS were generally mild and no serious adverse events occurred throughout the entire period of study. CONCLUSIONS: A combination of PNS and PBMNC transplantation appears to be a safe and effective treatment for patients with unreconstructable CLI. This combination may have great potential advantages in comparison with PBMNC transplantation alone and might constitute a novel therapeutic option for unreconstructable CLI.

Reviewing non clinical data for a granulocyte colony stimulatory factor product: experience in Brazil.

Non clinical studies are one of the requirements for the Brazilian National Regulatory Authority, ANVISA, for licensing a similar biotherapeutic product. During the WHO/KFDA workshop on implementing WHO guidelines on evaluating similar biotherapeutic products (SBP) in Seoul, Republic of Korea, the Brazilian experience with the non clinical studies of a Granulocyte Colony Stimulatory Factor (G-CSF), filgrastim, was presented. The applicant presented a reduced non clinical data package, but the key studies with relevant species were conducted and the non-clinical studies were considered sufficient for approval. Using the comparability exercise, these studies were taken together with the appropriate quality and clinical packages presented.

Safety and feasibility of autologous umbilical cord blood transfusion in 2 toddlers with cerebral palsy and the role of low dose granulocyte-colony stimulating factor injections.

PURPOSE: Cerebral palsy (CP) with a prevalence of 2.1 per 1,000 live births generates variable degrees of incurable developmental disability. The aim of the present report was to provide insight in the safety and feasibility of autologous umbilical cord blood (UCB) transfusion with low dose Granulocyte Colony Stimulating Factor (G-CSF) injections in improving the functional outcome of children with cerebral palsy. METHODS: Two toddlers with diagnosed CP were given autologous umbilical cord blood (UCB) transfusion accompanied by low dose subcutaneous granulocyte colony stimulating factor (G-CSF) injections. RESULTS: Gross Motor Function Classification System (GMFCS) improvements were seen in both without any side effects being noted to date. CONCLUSION: In this first report, autologous UCB based intervention in tandem with low dose sc G-CSF administration seems to be feasible and safe with encouraging functional outcome improvements in children with CP.

[Clinical study of kangai injection plus FLAG regimen for refractory/relapsed acute leukemia].

OBJECTIVE: To assess the efficacy and toxicity of the kangai injection combination of fludarabine (Flud), cytosine arabinoside (Ara-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) in refractory/relapsed acute leukemia (AL) patients. METHOD: From 2004 to 2010 in our hospital, the 49 cases of refractory/relapsed acute luekemia were randomly divided into treatment group (28 cases) and control group (21 cases). The control group were treated by kangai injection plus FLAG regimen, and the control group were treated by FLAG regimen. RESULT: The remission rate of treatment and total effective rate treatment group were 57.1% (16/28) and 71.4% (21/28), the control group were 52.3% (11/21) and 61.9% (13/21), there were no significant differences in the two groups. Duration of neutrophils less than 0.5 x 10(9)/L in treatment group was (14 +/- 6) day, control group was (23 +/- 3) day, Duration of platelet less than 25 x 10(9)/L in treatment group was (17 +/- 6) day, control group was (31 +/- 2) day, treatment group of III-IV degree of infection was 6.9% (1/28) and control group was 23.8% (5/21) between the two groups were significantly different (P < 0.05). treatment group of III- IV degree of gastrointestinal; toxicity was 10.7% (3/28) and control group was 28. 5% (6/ 21). CONCLUSION: Kangai injection plus FLAG regimen could increase the remission rate, shorten the period of bone marrow suppression, significantly reduced the incidence and degree of infection, play a important role in attenuated efficiency.

[Clinical study on acupuncture for leukopenia induced by chemotherapy].

OBJECTIVE: To explore the adjunctive therapeutic effects of acupuncture for leukopenia induced by chemotherapy. METHODS Eighty six cases with leukopenia after chemotherapy treatment were randomly divided into a granulocyte colony-stimulating factor (G-CSF) plus acupuncture (A) group and a G-CSF group, 43 cases in each group. After chemotherapy treatments, the patients of both groups were treated with G-CSF for 4 times, with acupuncture at Zhigou (TE 6), Quchi (LI 11), Hegu (LI 4), etc. added in the G-CSF plus A group, for an observaion cycle of 45 days. Their therapeutic effects on the 10th and 31st day and peripheral white blood cell (WBC) counts and neutrophilic granulocyte classification on the 10th, 17th, 24th, 45th day after treatment were compared. RESULTS: After they were treated on the 10th day, the effective rates were both 100.0% (both 43/43), and on the 31st day, the effective rate of 98.9% (42/43) in the G-CSF plus A group was higher than 91.1% (35/43) in the G-CSF group (P < 0.05). The WBC counts in the G-CSF plus acupuncture group were both higher than those in the G-CSF group on the 10th, 17th and 24th day after treatment (all P < 0.05). The ratios of mature neutrophilic granulocyte in the G-CSF plus A group were all higher than those in the G-CSF group at the same time (all P < 0.01). CONCLUSION: Acupuncture can increase the therapeutic effect of G-CSF, delay the decrease of WBC after discontinuing G-CSF, promote the neutrophilic granulocyte differentiating forward to mature and it is better for improving leukopenia induced by chemotherapy.

Use of pegfilgrastim support on day 9 to maintain relative dose intensity of chemotherapy in breast cancer patients receiving a day 1 and 8 CMF regimen

AIM: In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. METHODS: This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. RESULTS: Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. DISCUSSION: Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients (AU)

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Use of filgrastim and pegfilgrastim to support delivery of chemotherapy: twenty years of clinical experience.

Neutropenia is a serious hematologic toxicity of myelosuppressive chemotherapy. The discovery that granulocyte colony-stimulating factor (G-CSF) could stimulate the production of neutrophils was followed by the purification and molecular cloning of filgrastim (Neupogen), the human recombinant form of the protein, between 1984 and 1986. In this article, we review 20 years of clinical literature with filgrastim and the more recent experience with pegfilgrastim (Neulasta) to support the delivery of chemotherapy. The earliest clinical studies of filgrastim showed that it produces immediate transient leukopenia followed by a sustained, dose-dependent increase in circulating neutrophils. In the two registrational studies of filgrastim, the cumulative incidence of febrile neutropenia (FN) was reduced by about 50% compared with placebo. Subsequent clinical trials and meta-analyses established that primary prophylaxis with filgrastim (beginning in the first cycle of chemotherapy) reduced the incidence of FN, FN-related hospitalizations, intravenous anti-infective use, infection-related mortality, and the need for chemotherapy dose modification, compared with placebo or no treatment, in many tumor types. Pegfilgrastim, formed by the addition of a polyethylene glycol molecule to filgrastim, has comparable efficacy to filgrastim when administered only once per chemotherapy cycle. High-level evidence indicates that both filgrastim and pegfilgrastim improve the likelihood of completing dose-dense and dose-intense chemotherapy. The most recent guidelines from three international cancer organizations, the European Organization for Research and Treatment of Cancer, the American Society of Clinical Oncology, and the US National Comprehensive Cancer Network, are in agreement that filgrastim or pegfilgrastim should be given prophylactically when the risk of FN with a chemotherapy regimen is > or =20%, or when the risk is 10-20% and the patient has other risk factors for FN. The development of filgrastim and pegfilgrastim has revolutionized oncology practice. Prophylactic use of these agents has enabled development of more aggressive chemotherapy regimens, including dose-dense chemotherapy, and treatment of a broader range of patients.

Use of pegfilgrastim support on day 9 to maintain relative dose intensity of chemotherapy in breast cancer patients receiving a day 1 and 8 CMF regimen.

AIM: In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. METHODS: This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. RESULTS: Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. DISCUSSION: Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Inflammatory breast cancer outcome with epirubicin-based induction and maintenance chemotherapy: ten-year results from the French Adjuvant Study Group GETIS 02 Trial.

BACKGROUND: The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen. METHODS: One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed. RESULTS: The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome. CONCLUSIONS: FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC.

Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults.

PURPOSE: To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5 g m(-2), carboplatin 100 mg m(-2) and etoposide 150 mg m(-2), days 1-4, q 28 days, G-CSF 5 microg kg(-1) starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy. PATIENTS AND METHODS: Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60 min, T(max) 42 degrees C). RESULTS: The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months. CONCLUSION: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.

Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors.

PURPOSE: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. METHODS: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m(2) by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m(2) CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 microg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. RESULTS: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. CONCLUSIONS: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis.

OBJECTIVE: Potentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 microg x kg(-1) x day(-1), 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats. SETTING: University laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline. MEASUREMENTS AND MAIN RESULTS: Mortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 +/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p <.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p =.0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes). CONCLUSIONS: Granulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.