Prophylactic G-CSF Research Articles

Whole body hyperthermia combined with carboplatin/ paclitaxel in patients with ovarian carcinoma –Phase-II-study

5128 Background: Despite good treatment susceptibility to chemotherapy, ovarian carcinoma frequently leads to recurrent disease with unfavorable prognosis. Synergistic effects of carboplatin and Whole Body Hyperthermia (WBH) have been demonstrated in preclinical studies.Methods: In a phase-II-study we investigated the feasibility, safety and efficacy of standard regimen Carboplatin AUC 6/ Paclitaxel 175 mg/m2 (CT) combined with WBH. Between 1999 and 2001 9 patients were included (7 patients with primary ovarian carcinoma > FIGO 1c (after surgery) and 2 patients with late 1st recurrence. Paclitaxel was given on day 1 under normothermic conditions, on day 3, carboplatin was combined with WBH. Treatment was repeated every 3 - 4 weeks. Body temperature was maintained at 41.5–41.8 °C for one hour. All patients were analgosedated with midazolam and fentanyl. Primary prophylactic G-CSF was given from day 3 to 10. Patients with Hb < 12 received Erythropoetin 3x/ week. The WBH device used in this study was WBH 2000 (Oncotherm, Troisdorf, Germany). Median follow up was 33.8 months. Results: 53 courses of chemotherapy combined with WBH were performed (mean 5,9/ patient). Allergic reactions included 4 events of skin rash and 1 event of dyspnea, never leading to therapy stop. 2 cycles were given with dose reduction due to thrombopenia grade 3 (NCI) or severe emesis. Therapy was discontinued in 1 case due to thrombopenia grade 4. Neutropenia grade 3 (and no grade 4) was observed in 5.7 %. Thrombopenia grade 3 and 4 occurred in 1.9 % each. 30.2 % of the courses were accompanied by anemia grade 2, only 3.8 % by grade 3. Skin burning grade 1 occurred in 3 courses (5.7 %), grade 2 in 2 courses (3.8 %). All patients developed alopecia grade 2. 33.3% suffered from grade 1 polyneuropathy. The median disease free interval was 23.0 months (range 6.9 - 51.7 mon). 4 patients are still free of recurrent disease after a median of 47.1 months. Conclusions: Systemic cytostatic treatment with paclitaxel and carboplatin combined with WBH is feasible and adequately safe for the treatment of ovarian cancer. No significant financial relationships to disclose.

Prophylactic growth factor (GF) support with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) for node-negative breast cancer (BC): An interim safety analysis of the GEICAM 9805 study

620 Background: For patients (pts) with node-positive BC, TAC confers signficant disease-free and overall survival benefits vs FAC (5-fluorouracil, doxorubicin, cyclophosphamide), but with a higher rate of febrile neutropenia (Martin, SABCS 2003 ab 43). In our study of TAC vs FAC for node-negative BC, we performed an interim safety analysis to assess the impact of GF support on the incidence of TAC-related adverse events. Methods: Following surgery, patients (pts) with operable, high-risk (St Gallen, 1998), node-negative BC, 18–70 yr old, KPS ≥ 80%, and adequate hematologic and organ function were randomized to FAC (F 500 mg/m2, A 50 mg/m2, C 500 mg/m2) or TAC (T 75 mg/m2, A 50 mg/m2, C 500 mg/m2) day 1 every 3 wk for 6 cycles. After enrollment of 224 pts, the study was amended to require prophylactic G-CSF for pts subsequently treated with TAC, but not FAC. The present analysis assessed the impact of G-CSF on the incidence of febrile neutropenia (FN; fever ≥ grade 2 with gr 4 neutropenia) and other gr 3/...

A phase II study to evaluate the feasibility of bi-weekly docetaxel followed by bi-weekly doxorubicin and cyclophosphamide as adjuvant therapy for operable breast cancer (T-AC)

850 Background: Recent literature has supported dose dense therapy in the treatment of adjuvant breast cancer. This study sequences docetaxel(T) followed by doxorubicin(A) and cyclophosphamide(C). Docetaxel has shown to be superior to paclitaxel (P) as recently presented. This design demonstrates the feasibility of the most effective drugs, while minimizing toxicity. Methods: T-AC is an open label phase II trial sequencing docetaxel (100mg/m2) at 14 day intervals over 4 cycles followed by doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) at 14 day intervals over 4 cycles, for a total of 8 cycles with a 3 week break between drugs. Patients are supported with prophylactic G-CSF starting on day 2 of each cycle. Results: Seventeen of the 32 planned patients (pts.) have been enrolled. The first patient began therapy on 7/15/03. Currently, 3 patients have completed all 8 cycles, 8 have completed at least 4 cycles, and 6 have completed fewer than 4 cycles. The following Grade 3 and 4 toxicities have been experienced: 6 [Leukopenia]; 6 [Neutropenia]; 2 [Hand/Foot Syndrome]; 1 [Elevated ALT]; 1 [Elevated AST]; 1 [Infection with Neutropenia]. The table below shows the incidence of these Grade 3 and 4 Toxicities. Conclusions: One patient was removed from study due to progressive disease and accounts for two of the G4 toxicities and one of the G3 toxicities reported. Another patient was removed from study due to unresolved hand/foot syndrome and this is one of the G3 toxicities. The use of dose dense docetaxel followed by dose dense cyclophosphamide and doxorubicin in the adjuvant setting is feasible with acceptable toxicity based on the enrolled patient population. No significant financial relationships to disclose.

A phase II study to evaluate the feasibility of bi-weekly docetaxel followed by bi-weekly doxorubicin and cyclophosphamide as adjuvant therapy for operable breast cancer (T-AC)

850 Background: Recent literature has supported dose dense therapy in the treatment of adjuvant breast cancer. This study sequences docetaxel(T) followed by doxorubicin(A) and cyclophosphamide(C). Docetaxel has shown to be superior to paclitaxel (P) as recently presented. This design demonstrates the feasibility of the most effective drugs, while minimizing toxicity. Methods: T-AC is an open label phase II trial sequencing docetaxel (100mg/m2) at 14 day intervals over 4 cycles followed by doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) at 14 day intervals over 4 cycles, for a total of 8 cycles with a 3 week break between drugs. Patients are supported with prophylactic G-CSF starting on day 2 of each cycle. Results: Seventeen of the 32 planned patients (pts.) have been enrolled. The first patient began therapy on 7/15/03. Currently, 3 patients have completed all 8 cycles, 8 have completed at least 4 cycles, and 6 have completed fewer than 4 cycles. The following Grade 3 and 4 toxicities have been experienced: 6 [Leukopenia]; 6 [Neutropenia]; 2 [Hand/Foot Syndrome]; 1 [Elevated ALT]; 1 [Elevated AST]; 1 [Infection with Neutropenia]. The table below shows the incidence of these Grade 3 and 4 Toxicities. Conclusions: One patient was removed from study due to progressive disease and accounts for two of the G4 toxicities and one of the G3 toxicities reported. Another patient was removed from study due to unresolved hand/foot syndrome and this is one of the G3 toxicities. The use of dose dense docetaxel followed by dose dense cyclophosphamide and doxorubicin in the adjuvant setting is feasible with acceptable toxicity based on the enrolled patient population. No significant financial relationships to disclose.

Dose Escalation Study of Paclitaxel in Combination with Fixed-Dose Irinotecan in Patients with Advanced Non-Small Cell Lung Cancer (JCOG 9807)

Background: Both irinotecan (CPT) and paclitaxel (Pac) are effective against non-small cell lung cancer (NSCLC), and besides, preclinical studies have demonstrated an additive or synergistic interaction between camptothecin and taxane. Methods: We conducted a phase I/II study of combination chemotherapy consisting of Pac and CPT to determine qualitative and quantitative toxicities and efficacy of the combination against advanced NSCLC. We fixed the dose of CPT at 60 mg/m² and escalated the Pac dose in 10 or 20 mg/m² increments from a starting dose of 80 mg/m², and repeated the cycle every 2 weeks. Prophylactic G-CSF was also administered. Results: Between February 1999 and April 2001, 24 patients were registered in the study. None of the patients had a history of prior chemotherapy, but surgical resection had been performed in 3 of them. None of the patients experienced dose-limiting toxicity (DLT) up to and including level 6. At dose level 7 of Pac, 180 mg/m², 2 patients experienced DLT, that is grades 2 and 3 dyspnea due to pneumonitis. Another patient experienced grade 1 dyspnea due to pneumonitis. Neutropenia, diarrhea, and other toxicities were mild; however, we concluded that dose level 7 of Pac was the maximum-tolerated dose. An objective response was observed in 58.3%. The median survival time was 370 days, and the 1-year survival rate was 54.2%. Conclusion: Pneumonitis was the DLT in this study, and Pac 160 mg/m² and CPT 60 mg/m² every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.

Fourteen-Day CHOP Supported with Granulocyte Colony-Stimulating Factor in Patients with Aggressive Non-Hodgkin's Lymphoma: Results of a Phase II Study

The safety and efficacy of compressed-cycle (14-day) standard-dose CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) supported with prophylactic recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim) were evaluated in patients with aggressive non- Hodgkin's lymphoma (NHL). Patients with intermediate- or high-grade NHL (Working Formulation groups D-H and J; N = 120), accrued from 25 clinical practices, were given 6 cycles of standard-dose CHOP every 14 days. Granulocyte colony-stimulating factor 5 μg/kg was given daily subcutaneously in each cycle, starting on day 2 and continuing until the absolute neutrophil count was ≥ 10,000/μL. The overall response rate was 89%, with complete responses (CRs) in 52 of 120 patients (43%) and partial responses in 55 (46%). These results are consistent with previously reported outcomes from trials in this population. Of the 720 chemotherapy cycles planned for all patients, 615 (85%) were given on time at full dose. The median relative dose intensity (RDI) of cyclophosphamide and doxorubicin was 99%; the RDI of vincristine was 73%. In the 53 patients ≥ 60 years of age, 80% of the chemotherapy cycles were given on time at full dose, with median RDIs similar to those in the entire population. Response rates in the older patients were also similar, with CRs in 24 patients (45%) and partial responses in 21 (40%). Hematologic toxicity was significant but tolerable, with no treatment-related deaths. At a median follow-up of 20.6 months, 77% of patients were still alive. Standard-dose CHOP administered every 14 days with prophylactic G-CSF support was delivered as planned in most patients and produced response rates comparable with those with CHOP given every 3 weeks, without exceptional toxicity.

Phase I Study of Vinorelbine and Carboplatin Combination in Patients with Taxane and Anthracycline Pretreated Advanced Breast Cancer

Aim: To define the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the carboplatin-vinorelbine combination in pretreated patients with advanced breast cancer. Patients and Methods: Patients with histologically confirmed metastatic breast cancer relapsing or progressing after prior taxane and anthracycline containing chemotherapy were enrolled. Cohorts of 3–6 patients were treated at successive dose levels (DLs) with escalated doses of carboplatin [range, area under the curve (AUC) 4–6] on day 1 and vinorelbine (range, 20–35 mg/m²) on days 1 + 8 recycled every 28 days. Results: Twenty-seven patients with a median age of 58 years and performance status (WHO) of 0–2 were treated at 6 DLs. All patients were assessable for toxicity and 20 for response. DLT was reached at carboplatin 6 AUC and vinorelbine 35 mg/m², and therefore, this was considered as the MTD. Prophylactic G-CSF administration could not allow further dose escalation. The recommended dose for further phase II testing was defined at carboplatin 6 AUC on day 1 and vinorelbine 30 mg/m² on days 1 and 8. Among 98 administered treatment cycles 41 (42%) and 7 (7%) were complicated with grades 3 and 4 neutropenia and thrombocytopenia, respectively. Nonhematologic toxicities included grade 2 peripheral neuropathy in 3 cycles and grades 2 and 3 fatigue in 32 (32%). Conclusion: The present study determined the feasibility of the combination of carboplatin at AUC 6 (day 1) and vinorelbine at 30 mg/m² (days 1 and 8 ) without G-CSF support in patients with taxane and anthracycline pretreated advanced breast cancer. Phase II studies at these doses should follow in order to determine the activity of the regimen.

A randomised study of prophylactic G-CSF following MRC UKALL XI intensification regimen in childhood ALL and T-NHL

Background Despite the current widespread use of prophylactic G-CSF in children with solid tumours and leukaemia, its effectiveness has not been clearly demonstrated. This randomised study evaluates the role of G-CSF given after a 5-day intensification block in children with acute lymphoblastic leukaemia (ALL). Procedure Forty-six children with ALL or T-Cell non-Hodgkins lymphoma (NHL) treated on MRC ALL 97, UKALL XI or UKCCSG 9504 NHL protocols were randomised to receive granulocyte colony-stimulating factor following either the first or the second block of intensive chemotherapy in a cross-over study to determine if the prophylactic administration of G-CSF could reduce the rate of readmission to hospital for management of febrile neutropenia. Results There was a statistically significant difference in the rate of hospital admission in the group receiving prophylaxis, with 34 of 46 being admitted, compared to 42 of 46 patients in the control arm (74 vs. 91%; P = 0.0386). There were no differences found in duration of hospital admission, haematological toxicity, neutrophil recovery or duration of supportive care between the two groups. There was no demonstrable cost benefit derived from the prophylactic administration of G-CSF. Conclusions This study shows that the prophylactic administration of G-CSF following intensification chemotherapy for childhood ALL and T-NHL produces a significant reduction in the rate of readmission to hospital for the management of febrile neutropenia. Med Pediatr Oncol 2002;38:98–103. © 2002 Wiley-Liss, Inc.

Granulocyte Colony-Stimulating Factor in Induction Treatment of Children With Non-Hodgkin's Lymphoma: A Randomized Study of the French Society of Pediatric Oncology

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF; lenograstim) decreases the incidence of febrile neutropenia after induction courses in treatment of childhood non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Patients were randomized to receive (G-CSF+) or not receive (G-CSF−) prophylactic G-CSF, 5 μg/kg/d, from day 7 until an absolute neutrophil count ≥ 500/μL was sustained over 48 hours, after two consecutive induction courses of cyclophosphamide 1.5 or 3 g/m2, vincristine 2 mg/m2, prednisone 60 mg/m2/d × 5, doxorubicin 60 mg/m2, high-dose methotrexate 3 or 8 g/m2, and intrathecal injections (COPAD[M]) on protocols LMB89, LMT89, and HM91 of the French Society of Pediatric Oncology. RESULTS: One hundred forty-eight patients were assessable, 75 G-CSF+ and 73 G-CSF−. Although duration of neutropenia less than 500/μL was 3 days shorter in G-CSF+ patients (P = 10−4), incidence of febrile neutropenia (89% v 93% in the first course, 88% v 88% in the second course), durations of hos...

PCN3: PREDICTORS OF CHEMOTHERAPY-RELATED NEUTROPENIA: A REVIEW OF THE CLINICAL LITERATURE

OBJECTIVES: A literature review was conducted to identify risk factors and predictors of chemotherapy-related grade 3–4 and/or febrile neutropenia to assist with assessing who might benefit from treatments such as prophylactic G-CSF. METHODS: The literature review included publications from 1990–2000 of adults with any tumor type; 121 articles were identified that referenced risk factors or predictors for severe/febrile neutropenia. Study design, patient characteristics, chemotherapy treatment, and incidences of neutropenia were recorded. RESULTS: Twenty-one relevant publications, including prospective, retrospective, and modeling studies, were further analyzed. These articles yielded 27 potential risk factors/predictors in 3 categories: patient (n = 14), treatment-related (n = 8), and disease-related (n = 5) characteristics. Although most of the 27 potential risk factors/predictors were not validated to identify patients at higher risk for severe/febrile neutropenia, the review suggests that several simple-to-use and commonly available risk factors may be reliable predictors of neutropenia. These included low hemoglobin and neutrophil counts in cycle one; depth of the neutrophil nadir; low lymphocyte, monocyte and platelet levels; and a precipitous, early drop in blood cell counts. Several other risk factors, such as serum albumin 3.5g/dL on day 1, serum LDH> 1× normal alone or combined with bone marrow involvement, and high dose chemotherapy, also warrant further investigation. CONCLUSIONS: Few studies have explicitly explored risk factors associated with the occurrence of Grade 3–4 neutropenia. However, this literature review identified several common characteristics that may be measured with early and frequent CBC monitoring and may reasonably predict predisposition of patients to severe/febrile neutropenia.

Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients

To determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of docetaxel in combination with fixed doses of epirubicin. Women with locally advanced or metastatic breast cancer were given docetaxel, 60 mg/m2 in escalated doses by steps of 10 mg/m2, in association with two fixed doses of epirubicin (90 mg/m2, and 75 mg/m2). Since neutropenia was foreseen to be the most likely DLT, a third group with prophylactic G-CSF support was planned to define the MTD of docetaxel with 90 mg/m2 of epirubicin. Selected patients underwent pharmacokinetic evaluation of docetaxel. Fifty-eight patients entered the study. At the first step (90 mg/m2 of epirubicin) the MTD was obtained at 60 mg/m2 of docetaxel. At the second step (75 mg/m2 of epirubicin) the MTD of docetaxel was 80 mg/m2. At the third step (epirubicin 90 mg/m2) G-CSF allowed a safe escalation of docetaxel up to 90 mg/m2. Neutropenia was the most common hematological adverse event. Without G-CSF, grade 4 neutropenia occurred in 69% of cycles, of which 11% was complicated by fever. In G-CSF group, grade 4 neutropenia and neutropenic fever occurred in 31% and 3%, respectively. Most frequent non-hematological adverse effects were asthenia (45%), nausea (39%) and mucositis (36%). No patient developed congestive heart failure. Two toxic deaths occurred. Overall response rate was 73% in 42 out of 58 patients, with no apparent epirubicin dose-related effect. No statistically significant effect of the two doses of epirubicin was observed in docetaxel pharmacokinetics. On the basis of the toxicity profile, the docetaxel pharmacokinetics and the response rate observed, epirubicin 75 mg/m2 combined with docetaxel 80 mg/m2 can be recommended for further studies.

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy—results of a multicentric randomized German trial in advanced head-and-neck cancer

Purpose: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). Methods and Materials: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m 2/day)/carboplatinum (70 mg/m 2) on days 1–5 and 29–33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 μg, days 15–19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1–3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). Results: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT ( p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT ( p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT ( p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: ± G-CSF, p = 0.0072). Conclusion: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

Secondary Prophylactic G-CSF (Filgrastim) Administration in Chemotherapy of Stage I and II Hodgkin's Lymphoma with ABVD

The purpose of this study was to determine the effect of granulocyte colony-stimulating factor (filgrastim, G-CSF) for maintenance of chemotherapy dose-intensity in patients with stage I or II Hodgkin's lymphoma treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).Fifty-six patients with stage I or II Hodgkin's lymphoma treated with ABVD were eligible for secondary prophylactic G-CSF administration because of neutropenia (absolute neutrophil count < 1 × 109/L) causing treatment delay or febrile neutropenia. Patients received 300 μg (total dose) of G-CSF (filgrastim) subcutaneously on days 3 to 7 and 17 to 21 of each cycle in order to prevent dose reduction or delay in subsequent cycles of treatment continuing the G-CSF until completion of chemotherapy. Results showed that 30 (54%) of the patients required the use of G-CSF, 26 (47%) during the first or second cycle. After G-CSF administration delay in chemotherapy did not occur in 25 patients, whereas delays in the fifth or sixth cycle occurred in four patients. Despite treatment with G-CSF, one patient had febrile neutropenia. Dose intensity greater than 90% of that planned was delivered to more the 85% of patients.In conclusion: Secondary prophylactic G-CSF administration was necessary in more than half of patients with stage I or II Hodgkin's lymphoma during chemotherapy with ABVD. The use of G-CSF allowed maintenance of chemotherapy schedule and dose intensity in the majority of patients.

Prospective evaluation of a policy of early discontinuation of antibiotics and discharge from hospital in children with cancer who develop fever

Objective. To prospectively evaluate a set of clinical care schemata that would facilitate early discontinuation of antibiotics and hospital discharge in children with cancer admitted for management of infection. Methods. Based on recent published studies identifying children with fever and neutropenia who are at ‘‘low risk’’ for infection, and studies where antibiotics were discontinued quickly in such populations. We developed a set of four clinical schemata by which children with cancer would be managed at our institution. The schemata were prospectively evaluated over a period of 15 months. Results. The schemata were evaluated in 103 consecutive admissions in 69 children with cancer, admitted for treatment of presumed infection. In 61% of cases, children could be discharged home within 5 days of admission; only 9% was re-admitted within 7 days of discharge. In 77% of cases, children could be sent home on no antibiotics; in the remaining 23%, antibiotics could be narrowed in spectrum, and the majority sent home on an oral agent. Median length of stay for the entire cohort of patients was 5 days. In children receiving prophylactic G-CSF, the use of this agent did not impact on the length of stay, the need for subsequent re-admission, or the requirement for antibiotics at time of discharge. Conclusions. Early discontinuation of antibiotics and discharge from hospital is safe, provided that the child is clinically well and afebrile. Children with a clinical or microbiologic focus can have their spectrum of coverage narrowed, and can be safely discharged on oral agents. J Oncol Pharm Practice (2001) 6, 131-137.

Dose-escalation study of CHOP with or without prophylactic G-CSF in aggressive non-Hodgkin's lymphoma

CHOP is accepted as the gold standard for first line chemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalation study of CHOP was conducted to determine the maximal tolerated dose (MTD) and toxicity profile of CHOP at three-week intervals with or without prophylactic recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patients with aggressive NHL. The doses of drugs were escalated from 50 mg/m2 to 70 mg/m2 for doxorubicin and from 750 mg/m2 to 2250 mg/m2 for cyclophosphamide, with conventional doses of vincristine and oral prednisolone. After the MTD was determined without rHuG-CSF, dose escalation was conducted with prophylactic rHuG-CSF. Thirty-three patients with NHL were enrolled into the study. The MTD without prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 1250 mg/m2 of cyclophosphamide, with neutropenia as a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70 mg/m2 of doxorubicin and 2250 mg/m2 of cyclophosphamide. The overall response rate was 100% (76% complete response and 24% partial response). Progression-free survival and overall survival at five years were 45% and 66%, respectively. Significant dose escalation of doxorubicin and cyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy of dose-escalated CHOP should be compared with that of standard CHOP.

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer

BackgroundGemcitabine is active in patients with otherwise resistant or refractory ovarian cancer. As the drug is well tolerated, studies using gemcitabine combined with other anti-neoplastic agents are needed. The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methodsPatients with platinum-resistant or refractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800 mg/m2 day 1 and 8; 200 mg/m2 escalation per level) and epirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2 escalation per level) were given every 21 days for four to six cycles. G-CSF (filgrastim 5 ug/kg/die) was given in case of grade 4 neutropenia (levels without support) or from day 9 up to leukocyte count > 10,000/mm3 after nadir (levels with support). Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. MTD was determined first without and then with G-CSF. ResultsFour levels were studied (G 800 + E 60; G 1000 + E 60; G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and three patients enrolled, respectively. DLT (grade 4 febrile neutropenia) was observed in two patients at level 3. Thus, G1000 + E 60 mg/m2 was the MTD without G-CSF. The addition of prophylactic G-CSF did not allow a further increase of the dose and grade 4 thrombocytopenia was the DLT at level 4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in four patients. Among the 13 patients with measurable or evaluable disease, 3 partial responses were observed for an overall response rate of 23.1%. ConclusionsThe combination of gemcitabine 1000 mg/m (day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasible therapy. Grade 4 neutropenia is frequent and G-CSF support is often required. With prophylactic support of G-CSF, the DLT is thrombocytopenia.

The anti-inflammatory approach to septic shock

Our clinical experience with anti-inflammatory agents in patients with sepsis has been a disappointing one thus far. To better define the role of inflammation and the applicability of immunomodulators in sepsis, we have administered either anti-inflammatory (leukocyte adhesion complex directed monoclonal antibodies, CD11/18 MAb) or pro-inflammatory (recombinant granulocyte colony stimulating factor, G-CSF) agents in animals challenged with infectious or noninfectious inflammatory stimuli at intra- or extravascular sites. Inhibition of inflammation with CD11/18 MAb, reduced lung injury and improved survival with intravenous (TV) tumor necrosis factor (TNF) in canines. However, CD11/18 MAb with intrabronchial (IB) or intraperitoneal (IP) E. coli challenge, although improving lung injury with pneumonia, worsened host defense, hemodynamics and survival. In canines with IP or IB E. coli, or IV endotoxin, prophylactic G-CSF improved host defense, hemodynamics and survival. However, G-CSF with IB E. coli in the canine increased lung dysfunction and with a higher bacterial dose in the rat worsened both lung injury and survival. In additional studies in rats alone, the effects of prophylactic G-CSF on survival were fundamentally different, depending upon the site and the lethality of E. coli challenge. In a final study, canines were challenged with IP E. coli and then treated with G-CSF therapeutically. Despite using a range of doses, G-CSF did not improve any parameter of outcome in these studies and in very high doses appeared harmful. In our animal models, both pro- and anti-inflammatory agents had widely divergent effects on organ injury and survival. The disparate roles of inflammation in host defense and tissue injury may in part explain these results. Altering the inflammatory response during sepsis is more complicated than we originally expected. For pro- and anti-inflammatory agents to be maximally effective in clinical trials of sepsis, our animal data suggest that the influence of variables related to both the therapy (e.g. dose and timing) and the precipitating infection (e.g. severity, site and type) need to be clarified.

G-CSF for the prophylaxis of neutropenic fever in patients with small cell lung cancer receiving myelosuppressive antineoplastic chemotherapy: meta-analysis and pharmacoeconomic evaluation.

Standard meta-analytical and pharmacoeconomic techniques were used to study the clinical effectiveness and the cost-effectiveness ratio of the prophylactic (or pre-emptive) administration of G-CSF to patients with small cell lung cancer treated with conventional myelosuppressive cytotoxic chemotherapy. In the first part of our study, we conducted a meta-analysis of the randomized clinical trials evaluating G-CSF for this clinical indication. Three trials were identified by our literature search and were included in the meta-analysis (overall number of patients = 606). The end-points for evaluating G-CSF included mortality from infection and the cumulative incidence of neutropenic fever over six cycles of chemotherapy. The results of our meta-analysis demonstrate that prophylactic G-CSF did not affect mortality but significantly reduced the incidence of neutropenic fever from 68.3% to 38.7% (pooled odds ratio = 0.29, 95% CI: 0.21-0.40; P < 0.001). In the second part of our study, we carried out a pharmacoeconomic analysis to estimate the cost-effectiveness ratio of pre-emptive G-CSF (i.e. the 'average' cost associated with the prevention of an episode of neutropenic fever). This cost-effectiveness ratio was US$ 14,372 using the Italian price of the drug converted into dollars, or US$ 41 088 using the US price. Finally, we estimated the revenue-neutral price of G-CSF based on American data of the cost-of-illness. The price ranged from US$ 395 to US$ 569 per cycle, a figure higher than the value (US$ 150) previously reported in the literature.