Maintaining Dose Intensity Research Articles

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule

Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing. Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m(2), respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay. A total of 35 patients were treated. The MTD was docetaxel 30 mg/m(2) plus irinotecan 65 mg/m(2). Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease. The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.

Severe chemotherapy-induced diarrhea in patients with colorectal cancer: a cost of illness analysis

Diarrhea is common with many types of chemotherapy and can have a major impact on maintaining dose intensity and treatment effectiveness, and on overall health care resource consumption. In this study, a cost of illness analysis was conducted to estimate the overall economic impact of grade III/IV diarrhea in patients with colorectal cancer receiving adjuvant or palliative chemotherapy. This was a retrospective cohort study of patients with colorectal cancer who had received fluoropyrimidines, irinotecan or oxaliplatin (or a combination of these) and had developed grade III or IV diarrhea. Data collection included patient demographics, disease-related information and healthcare resource utilization to manage the grade III/IV diarrhea event (n=96). Grade III/IV diarrhea developed after the first cycle of chemotherapy in 54.2% of patients and was responsible for a median dose reduction and delay of 20% and 7 days, respectively. Overall, 31 of 96 patients (32.3%) required a hospital admission for supportive care with an 8-day median length of stay (range 2 to 28 days). When the economic impact of the grade III/IV diarrhea was quantified, the mean cost was Can 2559 dollars per patient (95%CI: 1665 to 3453 dollars). A logistic regression analysis identified grade IV diarrhea (OR 11.2; P<0.001) and severe diarrhea developing after the first chemotherapy cycle (OR 3.1; P=0.051) as being significantly associated with patient hospitalization. Grade III/IV diarrhea is a debilitating and costly complication of chemotherapy in colorectal cancer. Effective interventions that prevent the development of severe diarrhea need to be identified to save health-care costs and reduce patient morbidity.

Incidence of Febrile Neutropenia Is Low and Unrelated to Day 1 Neutrophil Count in Hodgkin's Lymphoma Treated with ABVD.

BACKGROUND: When neutropenia without infection is encountered while treating Hodgkin's Lymphoma (HL) with ABVD chemotherapy clinicians may choose to delay or reduce the chemotherapy dose or maintain the dose intensity and schedule with or without neutrophil growth factor support out of concern for neutropenic complications. We sought to determine the frequency of neutropenia and febrile neutropenia (FN) during ABVD chemotherapy.METHODS: We examined the medical records of all patients seen at Univ. of Iowa diagnosed with HL between 1/1/1990 and 12/31/2002 treated with ABVD chemotherapy. We reviewed the charts with complete chemotherapy dosing records to determine the incidence of neutropenia, dose reduction, dose delay and chart record of febrile neutropenia (FN).RESULTS: 218 patients were seen at UIHC with the diagnosis of HL. 104 patients were treated with ABVD chemotherapy. Adequate dosing data was available for 82 of these patients (894 treatments). On scheduled day of treatment (Day 1 and 15 of each cycle) at least Grade III neutropenia (ANC<1000) was present in 51 pts and 165 (18.45%) treatments. Grade IV (ANC<500) neutropenia was present in 28 pts and 56 (6.26%) treatments. Grade III/IV neutropenia was most frequent at treatment 2 (C1, D15) (n=32). Figure 1 illustrates the frequency of Grade III/IV neutropenia on day 1 of treatment. Dose modification (DM) defined as dose delay of > 4 days and/or dose reduction to < 80% of original doxorubicin dose following neutropenia occurred at only 10 of 165 treatments. No episodes of FN developed in this cohort. 155 treatments at the time of neutropenia were administered without dose reduction or dose delay. Growth factor support was co-administered in 55 (36.77%) of these treatments and the remaining treatments at the time of neutropenia (73.23%, n=100) were administered without growth factor support. One episode of FN developed in each of these subsets. No FN was observed following the 56 treatments administered with an ANC < 500, including 54 managed without DM (32 with GCSF support and 22 without). 672 treatments were administered with ANC ≥ 1000 resulting in 6 episodes of FN. DM was observed in 78 of these 672 treatments with 3 subsequent episodes of FN. 57 treatments (4 with DM, 23 with GCSF, 20 without GCSF, 14 unknown GCSF) had no available ANC data and were associated with one episode of FN. FN developed a total of 9 times in 8 of 82 patients over 894 treatments.CONCLUSION: Among HL patients treated with ABVD chemotherapy we found a high frequency of neutropenia - most commonly following treatment 1. We found a very low incidence of FN that was independent of neutropenia at the time of chemotherapy administration. Dose modification for neutropenia without infection at the time of ABVD administration is not required to reduce risk of FN, and should be avoided in settings where maintaining dose intensity is considered valuable. [Display omitted]

Long-Term Safety and Efficacy of Single Administration of a Fixed Dose Pegfilgrastim (Neulasta) in Inducing Neutrophil Count Recovery after ABVD Chemotherapy in Patients with Hodgkin Lymphoma.

Pegfilgrastim (Neulasta) is a pegylated form of G-CSF that has a long half-life allowing for a single administration per chemotherapy cycle. Although the safety and efficacy of pegfilgrastim has been established in association with chemotherapeutic regimens that are repeated every 3 weeks, its safety in patients receiving chemotherapy regimens every 2 weeks is currently under investigation. Of concern is the possibility of stem cell damage because of the long half life that may overlap with subsequent courses of chemotherapy. ABVD chemotherapy is widely used for the treatment of patients with Hodgkin disease. Up to 65% of patients receiving ABVD will require growth factor support to 1) maintain dose intensity 2) to prevent neutropenic fever and 3) to prevent delays in chemotherapy administration. In this study, we used a single dose per cycle of 6 mg pegfilgrastim in first and subsequent cycles of ABVD. Patients were eligible if they were older than 16 years and had previously untreated Hodgkin's disease patients who are scheduled to receive standard ABVD chemotherapy, adequate bone marrow reserve (ANC > 1,000/uL, Platelet > 100,000/uL, left ventricular ejection fraction > 50%, serum creatinine < 2 mg/dl, serum bilirubin < 2 mg/dl. They were excluded if they had HIV infection, were pregnant women and women or child bearing age who are not practicing adequate contraception, had prior chemotherapy, severe pulmonary disease including COPD and asthma, or history of prior sensitivity to E.coli derived products. All patients received one fixed dose of 6 mg pegfilgrastim 24 hours after ABVD therapy. CBC was performed on a weekly basis, until completion of therapy, and then was monitored every 3–4 months thereafter. Twenty-five patients are enrolled, all of whom are evaluable for efficacy and toxicity. Median age is 26 (range; 19 – 81 years). Men = 14, women = 11. Twenty three pts completed at least 3 full cycles (6 doses of ABVD), and thirteen Pts completed 6 cycles. A total of 225 doses of ABVD are administered. Day 14 ANC count below 1,000/uL occurred in only 5 doses of ABVD (2%). Non-neutropenic infection developed with 7 doses (3%) requiring delay in the subsequent dose of ABVD beyond day 14. Long-term safety is available on 11 pts who had a follow-up ANC counts beyond one year after completion of ABVD treatment. The median ANC after at least one year of follow up was 2,790/uL (range 1,350 to 7,060/uL). Five pts had a follow up beyond 18 months, and their median ANC was 2,300/uL (range: 1,570 to 3,360/uL). Furthermore, PK data from 5 unselected patients were performed on day 14 following the first cycle of ABVD. In all 5 patients, serum pegfilgrastim levels were below clinically significant levels. Our data demonstrate the efficacy of single dose per cycle of pegfilgrastim in maintaining ABVD dose intensity, keeping therapy on schedule, and preventing neutropenic fever. Furthermore, our preliminary long-term follow up data demonstrate the safety of pegfilgrastim administration in conjunction with standard dose chemotherapy given every 2 weeks.

Higher-Dose Imatinib (600 mg/Day) with Selective Intensification in Newly Diagnosed CML Patients in Chronic Phase; Cytogenetic Response Rates at 12 Months Are Superior to IRIS.

The IRIS trial demonstrated that imatinib at 400 mg/day was superior to alpha interferon as first line therapy for chronic phase CML. To assess the tolerability and efficacy of higher doses of imatinib in this setting we are conducting a Phase II trial (TIDEL) using imatinib 600 mg initially, increasing to 800 mg if specified response criteria are not met: complete hematologic response (CHR) at 3 Mo; major cytogenetic response (MCR) at 6 Mo; complete cytogenetic response (CCR) at 9 Mo, and >4 log reduction in BCR-ABL at 12 Mo. Filgrastim was used in cases of neutropenia to maintain dose intensity. Of 103 patients enrolled, 8 came off study in the first 12 Mo (2 unrelated deaths, 3 blast crisis, 3 poor response). 80 patients are currently assessable at 12 Mo (median age 47 years, range 21–75). Protocol mandated dose increases to 800 mg for failure to achieve MCR or CCR targets were activated in 7 patients before 12 months. We made a historical comparison of the best response by 12 Mo to responses in the IRIS trial (95% confidence intervals).Response rates at 12 MoMCR (0–35% Ph+)CCR (0% Ph+)MMR (≥3 log reduction in BCR-ABL)400mg - imatinib arm of IRIS n=55684.1% (81.0 – 87.2%)69.3% (65.3 – 73.2%)40% (NA)600mg - imatinib in TIDEL trial n=8094.2% (87.3 – 97.5%)88.5% (80.3 – 93.5%)47.4% (37.5 – 57.6%)P-value for z-test0.0004<0.0001NAPatients who had a mean daily dose (MDD) <600 mg in the first 2 months (n=27) had a CCR rate at 12 months of 78%, significantly lower than the 12 month CCR rate of 93% in patients receiving a MDD of 600 mg (n=75)(P=0.0015, log-rank test). Within the subgroup of patients receiving a MDD <600 mg in the first 2 Mo who subsequently received a MDD of 600 mg in months 2–6 the CCR rate at 12 Mo remained 73% (n=11) (P=0.004, log rank test). The probability of achieving MMR by 12 Mo was analysed according to the MDD of imatinib received in the first 6 Mo. Patients with a MDD of 600 mg had a probability of 58% (CI 45–71%) (n=62) of achieving MMR compared to 33% (CI 15–59%) in those with a MDD of 500 – 599 mg (n=17) and 32% in those with a MDD of <500 mg (n=20). Given these marked differences even at a MDD of 500–599 mg we looked at the median Sokal score in each group to see if more poor risk patients were present in the groups receiving reduced dose. Median Sokal scores for the groups with MDD of 600mg, 500–599 mg and <500 mg were no different − 0.94, 1.08; and 1.04 respectively. BCR-ABL mutations were detected in 7 patients within 12 Mo (2 had blast crisis, 1 lost CHR, 2 lost CCR and 2 maintain CCR on an increased imatinib dose). Mutation was the main cause of loss of response (5 of 8 patients). We conclude that cytogenetic response rates at 12 Mo are significantly superior to responses observed in the IRIS trial. Major molecular responses are frequent in the cohort able to tolerate a MDD of 600mg. The substantially lower rate of MMR in patients with a moderately reduced MDD was unexpected. These patients did not have less favourable CML biology based on Sokal scores. Although it is possible that other adverse prognostic factors were an influence in these patients, it suggests that dose intensity may be critically important to maximise molecular response.+

Efficacy and Late Effects of Stanford V Chemotherapy and Radiotherapy in Untreated Hodgkin's Disease: Mature Data in Early and Advanced Stage Patients.

From 5/89 to 5/01, 256 patients (pts) with classical Hodgkin's disease were treated on prospective trials with the weekly Stanford V (doxorubicin, vinblastine, mustard, vincristine, bleomycin, etoposide, prednisone) regimen +/− radiotherapy (RT). Pts with non-bulky stage I-IIA disease received 8 weeks Stanford V + 30 Gy involved field RT (G4 protocol, n=87) at Stanford (n=52) or Northern California Kaiser Permanente (n=35). Pts with bulky stage II (mediastinal mass > 1/3 intrathoracic diameter) or III,IV disease received 12 weeks Stanford V + 36 Gy to sites >=5 cm or macroscopic splenic disease (G2,3 protocol, n =169) at Stanford University. Bulky mediastinal pts received mediastinal, hilar and bilateral supraclavicular RT but no axillary or high neck RT to sites <5 cm. Chemotherapy was supported as needed by G-CSF to maintain dose intensity after the first dose reduction (absolute neutrophil count [ANC] < 1000/mm3) or treatment delay (ANC < 500/mm3). The median age was 29 years (range 16–60) and 134 pts were male. Two pts did not complete treatment: 1 due to sclerosing cholangitis not appreciated at diagnosis and 1 due to hyponatremia plus gastrointestinal toxicity. No cases of clinical bleomycin toxicity or radiation pneumonitis were observed. Major acute toxicities were grade 3–4 neutropenia and constipation. With a median follow-up of 5.7 years for early stage and 6.9 years for advanced stage pts, the outcome and late effects data are detailed in the table below. Among 24 pts with disease progression (4 with early stage and 20 {8 with international prognostic score >=4} with advanced stage disease, 16 (67%) were successfully treated with second-line therapy. Eleven pts have died: 6 from Hodgkin's disease and 1 each from suicide, complications of second-line transplantation, influenza, lung cancer, and unknown cause. No cases of secondary myelodysplasia/leukemia or non-Hodgkin's lymphoma have occurred. Second cancers included 1 prostate (no pelvic RT), 1 colon ( no abdominal RT but TBI used with second-line transplant), 1 lung (no RT) and 2 breast (1 with DCIS after mediastinal RT, 1 after axillary RT for >10 cm mass). To date, 72 post-treament conceptions (excluding pre-treament semen or embryo cryopreservation) were recorded with 65 live births (+ 4 current pregnancies) among 34 men and 30 women. In our hands, the Stanford V + RT regimen was effective with modest toxicity and 25% pts conceived post-treatment. An international score >=4 was the major adverse prognostic factor; the majority of relapses were successfully treated secondarily. These data support definitive testing of this treatment program as in the ongoing E2496 Intergroup Study for bulky and advanced stage disease.Efficacy and Late EffectsAll patientsFavorable I, IIBulky I, IIIII. IVn=256n=87n=61n=108FFP / 4 yr91% [87–95]*96% [92–100]92% [85–98]86% [79–93]FFP / 8 yr91% [91–94]96% [92–100]92% [85–98]86% [79–93]FFP / 12 yr89% [84–94]NA92% [85–98]83% [75–92]OS / 4 yr97% [94–99]98% [94–100]98% [93–100]95% [91–99]OS / 8 yr95% [92–98]98% [94–100]92% [82–100]95% [91–99]OS / 12 yr95% [92–98]NA92% [82–100]95% [91–99]AML/MDS0000Solid tumor5203*[95% confidence intervals]

Severe chemotherapy induced diarrhea (CID) in patients with colorectal cancer: A cost of illness analysis

6087 Background: Considerable cancer supportive care research has been devoted to febrile neutropenia, emesis and anemia. In contrast, diarrhea as a side effect of chemotherapy has received less attention. However, CID is common with many types of chemotherapy and can have a major impact on maintaining dose intensity, treatment effectiveness and on overall health care resources. In this study, a cost of illness analysis was conducted to estimate the overall economic impact of grade III/IV diarrhea in patients with colorectal cancer receiving chemotherapy. Methods: This was a retrospective cohort study consisting of patients with colorectal cancer that had received chemotherapy and had developed grade III or IV diarrhea. Data collection included patient demographics, disease related information and healthcare resource utilization to manage the grade III/IV CID event. Multivariable logistic regression analysis was then used to identify factors associated with hospitalization for uncontrolled CID. Results: P...

Severe chemotherapy induced diarrhea (CID) in patients with colorectal cancer: A cost of illness analysis

6087 Background: Considerable cancer supportive care research has been devoted to febrile neutropenia, emesis and anemia. In contrast, diarrhea as a side effect of chemotherapy has received less attention. However, CID is common with many types of chemotherapy and can have a major impact on maintaining dose intensity, treatment effectiveness and on overall health care resources. In this study, a cost of illness analysis was conducted to estimate the overall economic impact of grade III/IV diarrhea in patients with colorectal cancer receiving chemotherapy. Methods: This was a retrospective cohort study consisting of patients with colorectal cancer that had received chemotherapy and had developed grade III or IV diarrhea. Data collection included patient demographics, disease related information and healthcare resource utilization to manage the grade III/IV CID event. Multivariable logistic regression analysis was then used to identify factors associated with hospitalization for uncontrolled CID. Results: Patients (n=96) had a mean age of 60.3 years and 49% of the sample was receiving adjuvant chemotherapy with a curative intent. The severe CID developed after the first cycle of chemotherapy in 54.2% of patients and was responsible for a median dose reduction and delay of 20% and 7 days respectively. Overall, 30 of 96 patients (31%) with severe CID required a hospital admission for supportive care with an 8-day median length of stay (range = 2 to 28 days). There were 2 deaths with 1 possibly being related to the diarrhea. When the economic impact of the grade III/IV CID was quantified, the mean cost was $2,559 per patient (95%CI: $1,665 to $3,453). The logistic regression analysis identified grade IV diarrhea (OR=9.9; P < 0.001) and severe CID developing after the first chemotherapy cycle (OR=3.6; P = 0.026) as significant predictors of patient hospitalization. Conclusions: Grade III/IV diarrhea is a debilitating and costly complication of chemotherapy in colorectal cancer. Effective interventions that prevent the development of severe CID need to be identified to save health care costs and reduce patient morbidity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Canada

The role of growth factor support following neutropenic events in early stage breast cancer (BC) patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC): A sub-analysis of BCIRG 001

677 Background: TAC significantly improves disease-free and overall survival over FAC (HR 0.70, 0.68, respectively) and is emerging as one of the most active adjuvant treatments in patients (pts) with node positive early stage (BC) (Martin, SABCS 2003 #43). TAC is generally well tolerated but is associated with a higher incidence of febrile neutropenia (FN) vs FAC. ASCO clinical practice guidelines recommend secondary prophylaxis with G-CSF after FN in a prior cycle to maintain dose intensity. Methods: Pts with node-positive BC were randomized to TAC (75/50/500 mg/m2 q3wk x 6) or FAC (500/50/500 mg/m2 q3wk x 6). Corticosteroid premedication and prophylactic ciprofloxacin were given with TAC, but not with FAC. In case of FN (≥ gr 2 fever with gr 4 neutropenia), pts were treated with G-CSF for all subsequent cycles. This retrospective sub-group analysis compares the incidence of FN for cycles treated without and with G-CSF. Results: 1491 patients were accrued with 1480 evaluable for safety (TAC 744, FAC 736). A similar number of cycles were delivered in both arms (TAC 4010; FAC 4007). FN: TAC 183 pts (24.7% pts, 5.4% cycles), FAC 18 pts (2.5% pts, 0.5% cycles) with at least half the FN occurring in the first cycle (TAC: 97/183 pts; FAC 9/18 pts). G-CSF was administered to 250 TAC pts and 93 FAC pts. Among these, G-CSF was used as secondary prophylaxis for 87% (TAC) and 44% (FAC) of pts. The rate of FN (per cycle) without vs with G-CSF (+G) among all pts was: TAC 187/3114 (6.0%) vs TAC+G 28/896 (3.1%); FAC 19/3704 (0.5%) vs FAC+G 1/303 (0.3%). There were no septic deaths during treatment with either TAC or FAC, regardless of the use of GCSF. Conclusions: Among pts treated with TAC, the use of G-CSF decreased the incidence of neutropenic complications, although it remained higher than for pts treated with FAC. For pts experiencing a neutropenic event with TAC, secondary prophylaxis with G-CSF is appropriate. The impact of G-CSF on other clinical safety parameters will also be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis

The role of growth factor support following neutropenic events in early stage breast cancer (BC) patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC): A sub-analysis of BCIRG 001

677 Background: TAC significantly improves disease-free and overall survival over FAC (HR 0.70, 0.68, respectively) and is emerging as one of the most active adjuvant treatments in patients (pts) with node positive early stage (BC) (Martin, SABCS 2003 #43). TAC is generally well tolerated but is associated with a higher incidence of febrile neutropenia (FN) vs FAC. ASCO clinical practice guidelines recommend secondary prophylaxis with G-CSF after FN in a prior cycle to maintain dose intensity. Methods: Pts with node-positive BC were randomized to TAC (75/50/500 mg/m2 q3wk x 6) or FAC (500/50/500 mg/m2 q3wk x 6). Corticosteroid premedication and prophylactic ciprofloxacin were given with TAC, but not with FAC. In case of FN (≥ gr 2 fever with gr 4 neutropenia), pts were treated with G-CSF for all subsequent cycles. This retrospective sub-group analysis compares the incidence of FN for cycles treated without and with G-CSF. Results: 1491 patients were accrued with 1480 evaluable for safety (TAC 744, FAC 736...

Colony-stimulating factors for the management of neutropenia in cancer patients.

Neutropenia and its subsequent infectious complications represent the most common dose-limiting toxicity of cancer chemotherapy. Febrile neutropenia (FN) occurs with common chemotherapy regimens in 25 to 40% of treatment-naive patients, and its severity depends on the dose intensity of the chemotherapy regimen, the patient's prior history of either radiation therapy or use of cytotoxic treatment, and comorbidities. The occurrence of FN often causes subsequent chemotherapy delays or dose reductions. It may also lengthen hospital stay, increase monitoring, diagnostic and treatment costs, and reduce patient quality of life. A decade after their introduction, colony-stimulating factors (CSFs) such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are now an integral part of the prevention of potentially life-threatening FN; however, only G-CSF has US Food and Drug Administration approval for use in chemotherapy-induced neutropenia. These adjunctive agents accelerate formation of neutrophils from committed progenitors, thereby reducing the duration and severity of neutropenia. Important uses of CSFs in oncology are prevention of FN after chemotherapy, treatment of febrile neutropenic episodes and support following bone marrow transplantation, and collection of CSF-mobilised peripheral blood progenitor cells. G-CSF is used more frequently than GM-CSF for all of these indications because of fewer associated adverse effects. Clinical trials to date have not demonstrated a significant effect on overall survival or disease-free survival, which is most likely to be due to small sample size and lack of power to prove effect. However, they have demonstrated clinical utility in allowing the delivery of planned chemotherapy dose on schedule, an important clinical goal especially in curative tumour settings. The high cost of these agents limits their widespread use. Current American Society of Clinical Oncology guidelines recommend primary prophylaxis, or first cycle use, with CSFs being confined to patients with > or = 40% risk of FN, which may include elderly patients and other high-risk patients. In addition to the risk of FN, primary prophylaxis should also be considered if the patient has risk factors that place them in the Special Circumstances category. These risk factors may include decreased immune function in patients who are already at an increased risk of infection and pre-existing neutropenia due to disease, extensive prior chemotherapy, or previous irradiation to the pelvis or other areas containing large amounts of bone marrow. Future studies are needed to better define the patients most likely to benefit from CSF therapy, both for prophylaxis and as an adjunct to antibiotics for treatment of FN. Other potential uses include combination therapy with stem cell factors and other cytokines to boost progenitor cell development, maintaining dose intensity of salvage therapy in metastatic cancer patients, and application in patients with pneumonia, Crohn's fistulas, diabetic foot infections and a variety of other infectious conditions.

Treatment of the jaundiced patient with breast carcinoma

BACKGROUND Breast carcinoma in the setting of liver metastases and jaundice raises a complex therapeutic dilemma. Not only is the prognosis poor but toxicity related to treatment can be unpredictable due to altered drug clearance. Guidelines built around dose reduction have been suggested but often do not address the varied presentations in clinical medicine. Bilirubin exceeding 5.0 mg% often is considered an absolute contraindication to the administration of chemotherapeutic agents dependent on hepatic metabolism. METHODS A 55-year-old woman with metastatic breast carcinoma to the liver and hyperbilirubinemia was treated with sequential, empiric chemotherapy agents with the goal of preventing severe toxicity through dose reduction, avoidance of combination therapy, divided doses (weekly therapy), and selection of drugs less dependent on hepatic clearance. Several attempts did not yield a regimen with a successful response, but toxicity was minimal. Eventually, a successful schedule and dose of an agent cleared by liver metabolism was individualized for the patient. RESULTS After eight cycles of low dose weekly doxorubicin chemotherapy, the patient's symptoms resolved, bilirubin level normalized, and performance status returned to baseline. The patient remained on treatment and was alive 12 months later. CONCLUSIONS The authors propose that altering a drug schedule by dividing doses may minimize toxicity, maintain dose intensity, and represent an alternative strategy for the treatment of patients with hepatic impairment. Cancer 2001;91:660–3. © 2001 American Cancer Society.

Treatment of the jaundiced patient with breast carcinoma

Breast carcinoma in the setting of liver metastases and jaundice raises a complex therapeutic dilemma. Not only is the prognosis poor but toxicity related to treatment can be unpredictable due to altered drug clearance. Guidelines built around dose reduction have been suggested but often do not address the varied presentations in clinical medicine. Bilirubin exceeding 5.0 mg% often is considered an absolute contraindication to the administration of chemotherapeutic agents dependent on hepatic metabolism. A 55-year-old woman with metastatic breast carcinoma to the liver and hyperbilirubinemia was treated with sequential, empiric chemotherapy agents with the goal of preventing severe toxicity through dose reduction, avoidance of combination therapy, divided doses (weekly therapy), and selection of drugs less dependent on hepatic clearance. Several attempts did not yield a regimen with a successful response, but toxicity was minimal. Eventually, a successful schedule and dose of an agent cleared by liver metabolism was individualized for the patient. After eight cycles of low dose weekly doxorubicin chemotherapy, the patient's symptoms resolved, bilirubin level normalized, and performance status returned to baseline. The patient remained on treatment and was alive 12 months later. The authors propose that altering a drug schedule by dividing doses may minimize toxicity, maintain dose intensity, and represent an alternative strategy for the treatment of patients with hepatic impairment.

Docetaxel and Gemcitabine in Anthracycline-Resistant Advanced Breast Cancer: A Hellenic Cooperative Oncology Group Phase II Study

A phase II study was conducted to evaluate the activity and toxicity profile of the combination of docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer (ABC). Thirty-nine eligible patients with a median performance status of I (range, 0–2) were enrolled in the study. Treatment consisted of docetaxel 75 mg/m2 in a 1-hr infusion on day 1 preceded by gemcitabine 1000 mg/m2 over 30 min on days 1 and 8. One hundred eighty-one treatment cycles were administered, 113 (62.4%) of them at full dose. Relative dose intensity of gemcitabine and of docetaxel was 0.73 and 0.85, respectively. More common grade 3–4 toxicities included neutropenia (49%), anemia (10%), fatigue (10%), nausea/vomiting (8%), and alopecia (77%). Seven patients were hospitalized for febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was required in 90% of patients. Overall, 14 patients (36%) responded, 3 (7.5%) of them completely. Median duration of response was 10.3 months (range, 4.6–17.5+). Median time to progression was 7 months (range, 0.2–17.5+) and median survival 12.7 months (range, 2-–20.5+). In conclusion, the combination of docetaxel and gemcitabine, as used in the present study, has moderate activity in anthracycline-resistant ABC. Future studies should incorporate prophylactic administration of G-CSF to reduce the incidence of febrile neutropenia and maintain dose intensity.

Oprelvekin (Neumega®)

Objective. Our objective was to review oprelvekin, which is a new thrombopoietic cytokine approved in the United States to prevent severe thrombocytopenia and reduce the number of platelet transfusions after myelosuppressive chemotherapy. This article focuses on oprelvekin’s pharmacology, pharmacokinetics, and place in therapy. Data Sources. A search of the National Cancer Institute-sponsored Cancerlit database from 1963 to 1999 was completed. Subject mesh headings that were searched included interleukin-11, oprelvekin, breast cancer, chemotherapy dose intensity, and cancer pharmacoeconomics. Data were also collected from the package insert and from Genetics Institute (Cambridge, MA) publications. Study Selection. Searches were limited to studies with humans, which included clinical trials, news articles, and review articles. After reading all of the human clinical trials, additional pertinent citations were obtained and read. Data Synthesis. Oprelvekin has been studied in both adults and children, with the bulk of the data coming from the treatment of women with breast cancer. A phase I study in adults evaluated doses of 10, 25, 50, 75, and 100 mg/kg/day and determined the maximum tolerated dose to be 50 mg/kg/day. The toxicity seen with the 75 and 100 mg/kg/day doses includes constitutional symptoms (arthralgias, myalgias, fatigue, nausea, and headache) and a cerebral vascular accident. Phase II and III trials showed that 25-50 mg/kg/day effectively reduced the number of patients requiring platelet transfusions and decreased the number of platelet transfusions after chemotherapy. Pharmacokinetics performed with the 50 mg/kg/day subcutaneous (s.c.) dose resulted in a maximum sera concentration of 17.4 6 5.4 ng/mL, which occurred at 3.2 6 2.4 hours. The terminal half-life was 6.9 6 1.7 hours. Clearance decreases with increasing age, and pediatric patients have a 1.2- to 1.6-fold higher clearance than adults. These pharmacokinetic parameters led to a dosing recommendation of 75- 100 mg/kg/day in pediatric patients. Due to the high cost of oprelvekin and the lack of data demonstrating that it affects mortality, its role in current therapies is unclear. It is currently being promoted to maintain dose intensity in patients with breast cancer, testicular cancer, and lymphoma. Depending upon institutional platelet and oprelvekin costs, it may also be useful in patients receiving a large number of platelet transfusions. Thus far, it has not demonstrated efficacy in bone marrow transplant patients. Conclusion. Oprelvekin can effectively prevent the need for platelet transfusion in nontransplant patients receiving myelosuppressive chemotherapy. Due to its high cost, it will most likely be used to maintain chemotherapy dose intensity, which may translate into a survival advantage.

Single-Dose Granulocyte Colony-Stimulating Factor Concomitant with Multifractionated Dose Chemotherapy: A Strategy for Maintaining Dose Intensity

Multifractionated dosing (MFD) schedules for chemotherapy administration such as weekly or twice weekly administration are intended to maximize dose intensity while minimizing toxicity, but the cumulative drug effect may result in neutropenia necessitating interruption of dose fractions and thereby compromising dose intensity. Intermittent granulocyte colony-stimulating factor (G-CSF, Neupogen®, Am-gen) was administered to patients receiving MFD on three paclituxel-based chemotherapy regimens. Single-dose G-CSF was administered concomitant with the chemotherapy dose fraction when the white blood count was between 2000 and 3500 cells/μl. A retrospective analysis of the concomitant administration of single-dose G-CSF with chemotherapy in these trials demonstrated that in most patients, G-CSF administration guided by rhe level or grade of leukopenia permitted maintenance of the chemotherapy dose intensity and completion of the treatment cycle. The common pattern in a six-dose, twice weekly, multifractionated cycle was for G-CSF to be administered with every other chemotherapy dose beginning with the third, fourth, or fifth dose, but some courses required G-CSF administration with each chemotherapy dose fraction. Guidelines for the concomitant use of G-CSF and paclitaxel-based MFD chemotherapy can be used to maintain chemotherapy dose intensity. A prospective study of guidelines for cytokine usage developed on the basis of this retrospective study will be necessary to determine the optimal cytokine dose and schedule for use simultaneously with chemotherapy.

Frequent Dose Delays and Growth Factor Requirements with the Sequential Doxorubicin-CMF Schedule

Doxorubicin for four cycles plus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for eight cycles is an effective adjuvant regimen for breast cancer patients with more than three involved axillary lymph nodes. We reviewed the incidence of dose delays and growth factor requirements when this regimen is administered to patients receiving concurrent irradiation. Thirty-six patients with more than three involved axillary lymph nodes were treated with the sequential regimen doxorubicin-CMF and irradiation. Patients with two or more dose delays G-CSF treatment. Seventy-five percent of the patients required dose delays for day-22 neutropenia, and growth factors were needed for half of the patients in order to maintain a dose intensity of 0.940. The first delayed cycle occurred in 74% of the patients while receiving concomitant chemoradiotherapy. Frequent dose dealys were required when the sequential regimen doxorubicin-CMF was administered along with radiotherapy. Growth factors are needed to maintain dose intensity similar to that achieved in the original trial.

Intermittent G-CSF to maintain dose intensity of chemotherapy for Hodgkin's disease.

As the ability to deliver full dose chemotherapy on time in Hodgkin's disease has been reported to be an important determinant of response,1 our department has adopted a policy of using G-CSF in patients receiving adriamycin, bleomycin, vinblastine and dacarbazine (ABYD) in whom neutropenia would otherwise necessitate dose reduction or delay. This is based on reports that G-CISF following myelosuppressive chemotherapy reduces the period of neutropenia, resulting in less fever2 and the ability to deliver multiple courses of full-dose treatment without delay.3 In these reports, G-CSF was administered daily, but whether this represents the optimal schedule for this purpose has yet to be established.

Human recombinant granulocyte-macrophage colony-stimulating factor in pediatric oncology practice.

This paper reports preliminary experiences with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) in children with malignant diseases administered for three indications: (1) chemotherapy-induced neutropenia and sepsis, (2) prolonged neutropenia decreasing dose intensity, and (3) prevention of neutropenia after sublethal doses of chemotherapy. It was concluded that in the daily dose of 5 micrograms/kg subcutaneously, GM-CSF is capable of reducing the duration of chemotherapy-induced neutropenia and may be an effective tool in maintaining dose intensity and achieving dose escalation.

Cytokine efficiency in the treatment of high-grade malignant non-Hodgkin's lymphomas: Results of a randomized double-blind placebo-controlled study with intensified COP-BLAM ± rhGM-CSF

In high-grade malignant non-Hodgkin's lymphomas (hNHL) recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was evaluated as support to chemotherapy. In a phase III trial, 172 patients (age 18-73 years, stage II-IV) were risk-stratified according to LDH levels and lymphoma size and randomized to receive rhGM-CSF (400 micrograms) (87 patients) or placebo (85 patients) subcutaneously days 8-14 of each cycle of an intensified COP-BLAM regimen. RhGM-CSF significantly reduced the length and nadir of neutropenia, the length of fever episodes, the frequency of all and of severe infections, and of hospitalization and antibiotic requirements. Complete response rates were 63% for all patients and 64% vs. 61% (n.s.) in the rhGM-CSF vs. the control group. Deviations from protocol in applied dosages of myelotoxic drugs and in cycle intervals maintained differed slightly in favor of the rhGM-CSF arm. However, there were no significant differences in overall survival between the GM-CSF treatment and control groups (21 vs. 23 months). Early relapse rates were markedly lower than in the standard-dose COP-BLAM/IMVP-16 regimen. Thus, GM-CSF abates toxic side effects of chemotherapy and may help to maintain dose intensity in high-risk hNHL.