Pediatric Sarcoma Patients Research Articles

Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel

10059 Background: Cure rates for children andadolescent's cancer have improved steadily for most tumor types. However, recurrent disease or progressive-refractory sarcomas remain incurable and most of these patients die within 1 to 2 years after diagnosis. In this report we describe experience with gemcitabine-docetaxel (G+D) in pediatric patients with relapsed or refractory sarcomas. Methods: Ten relapsed/refractory pediatric sarcoma patients including 6 Ewing sarcoma, 2 synovial sarcoma, 1 osteosarcoma, and 1 undifferentiated sarcoma were treated in an outpatient setting with gemcitabine 1000 mg/m2 over 90 minutes on day 1 and 8, and docetaxel 100 mg/m2 ver 3 to 4 hours on day 8 of a 21-day cycle, as an investigational rescue therapy. Results: A median of 7 cycles were given per patient (range, 4 to 10), and a total of 70 cycles were administered. To date, 2 patients continue on treatment. All symptomatic patients responded clinically to this regimen. No grade 3–4 toxicities were encountered. Five patients (50%) had a CR/functional CR, 4 patients (40%) had a PR/SD, and 2 patients (20%) had PD, which provides an overall response rate (CR+PR/SD) of 90%. Prolonged disease stabilization was achieved even for multiple relapsed patients with the G + D regimen, median duration of responses 11 months. Five out of the 10 patients (50%) are alive, median follow-up 48 months from diagnosis. Conclusions: The G + D regimen seems to be active against advanced pediatric sarcomas. It does not exacerbate pre-existing toxicities and allows good quality of life. Evaluation in a large, formal phase II trial for ES patients is ongoing. No significant financial relationships to disclose.

Treatment Planning and Delivery of External Beam Radiotherapy for Pediatric Sarcoma: The St. Jude Children's Research Hospital Experience

To describe and review the radiotherapy (RT) treatment planning and delivery techniques used for pediatric sarcoma patients at St. Jude Children's Research Hospital. The treatment characteristics serve as a baseline for future comparison with developing treatment modalities. Since January 2003, we have prospectively treated pediatric and young-adult patients with soft-tissue and bone sarcomas on an institutional Phase II protocol evaluating local control and RT-related treatment effects from external-beam RT (conformal or intensity-modulated RT; 83.4%), low-dose-rate brachytherapy (8.3%), or both (8.3%). Here we describe the treatment dosimetry and delivery parameters of the initial 72 patients (median, 11.6 years; range, 1.4-21.6 years). Cumulative doses from all RT modalities ranged from 41.4 to 70.2 Gy (median, 50.4 Gy). Median D(95) and V(95) of the planning target volume of external-beam RT plans were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the primary phase and 97.8% and 99.2% for the cone-down/boost phase. The dose-volume histogram statistics for 27 critical organs varied greatly. The spinal cord in 13 of 36 patients received dose >45 Gy (up to 52 Gy in 1 cc) because of tumor proximity. Planning and delivery of complex multifield external beam RT is feasible in pediatric patients with sarcomas. Improvements on conformity and dose gradients are still desired in many cases with sensitive adjacent critical structures. Long-term follow-up will determine the risk of local failure and the benefit of normal tissue avoidance for this population.

249: Prolonged Survival for Ultra High-Risk Pediatric Sarcoma Patients following Reduced-Intensity Allogeneic Stem Cell Transplantation (AlloSCT)

249: Prolonged Survival for Ultra High-Risk Pediatric Sarcoma Patients following Reduced-Intensity Allogeneic Stem Cell Transplantation (AlloSCT)

Positron Emission Tomography for Staging of Pediatric Sarcoma Patients: Results of a Prospective Multicenter Trial

The objective of this study was to evaluate the impact of positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose (FDG) for initial staging and therapy planning in pediatric sarcoma patients. In this prospective multicenter study, 46 pediatric patients (females, n = 22; males, n = 24; age range, 1 to 18 years) with histologically proven sarcoma (Ewing sarcoma family tumors, n = 23; osteosarcoma, n = 11; rhabdomyosarcoma, n = 12) were examined with conventional imaging modalities (CIMs), including ultrasound, computed tomography (CT), magnetic resonance imaging, and bone scintigraphy according to the standardized algorithms of the international therapy optimization trials, and whole-body FDG-PET. A lesion- and patient-based analysis of PET alone and CIMs alone and a side-by-side (SBS) analysis of FDG-PET and CIMs were performed. The standard of reference consisted of all imaging material, follow-up data (mean follow-up time, 24 +/- 12 months), and histopathology and was determined by an interdisciplinary tumor board. FDG-PET and CIMs were equally effective in the detection of primary tumors (accuracy, 100%). PET was superior to CIMs concerning the correct detection of lymph node involvement (sensitivity, 95% v 25%, respectively) and bone manifestations (sensitivity, 90% v 57%, respectively), whereas CT was more reliable than FDG-PET in depicting lung metastases (sensitivity, 100% v 25%, respectively). The patient-based analysis revealed the best results for SBS, with 91% correct therapy decisions. This was significantly superior to CIMs (59%; P < .001). In staging pediatric sarcoma, subsidiary FDG-PET scanning depicts important additional information and has a relevant impact on therapy planning when analyzed side-by-side with CIMs.

Re: Loss of antibody titers and effectiveness of revaccination in post‐chemotherapy pediatric sarcoma patients

Re: Loss of antibody titers and effectiveness of revaccination in post‐chemotherapy pediatric sarcoma patients

Re: Loss of antibody titers and effectiveness of revaccination in post‐chemotherapy pediatric sarcoma patients—Response

Re: Loss of antibody titers and effectiveness of revaccination in post‐chemotherapy pediatric sarcoma patients—Response

Loss of antibody titers and effectiveness of revaccination in post‐chemotherapy pediatric sarcoma patients

Little is known about the effects of chemotherapy on patient antibody titers to vaccine-preventable infectious diseases; thus, there is no standard protocol for revaccinating post-chemotherapy patients. To assess losses of detectable antibody titers due to chemotherapy, we retrospectively examined antibody titers for tetanus, varicella, measles, mumps, rubella, hepatitis B, and polio in 109 pediatric sarcoma patients. We also evaluated revaccination data to determine current practices and efficacy of revaccination. We limited our sample to osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma patients to control for the chemotherapy regimen patients received. Patients had pre-treatment detectable antibody titer that fell within the range of healthy children's antibody titers. However, 71% of patients had post-chemotherapy negative titers for at least one infectious disease. Patients most commonly had negative titers for hepatitis B (64%). Few patients had negative titers for measles (14%), mumps (9%), rubella (4%), polio 1 (0%), polio 2 (2.9%), polio 3 (4.8%), tetanus (5%), or varicella (11%). Revaccinations most frequently administered were hepatitis B and polio. Our findings suggest that post-chemotherapy patients may need to be revaccinated against certain vaccine-preventable diseases including hepatitis B, tetanus, varicella, polio, measles, mumps, and rubella. Larger studies need to be performed to establish guidelines for revaccinating post-chemotherapy pediatric patients.

What Is Quality of Life in Children with Bone Sarcoma?

Quality of life measures have neglected to include a critical self-assessment component in pediatric sarcoma patients. Our report shows how children rate their own quality of life and how that varies over time after surgery. Using the Pediatric Outcomes Data Collection Instrument, quality of life data was prospectively collected and combined with a retrospective review of clinical parameters on 43 children with primary bone sarcoma, with an average followup of 3 years. Children reported good yet variable scores in five of the six domains. Lower scores were noted in the Sports/Physical Functioning domain, particularly in the first 12 months after surgery, with improvement seen up to 24 months after surgery. Tumor specific factors such as size larger than 8 cm and lower extremity location were negative predictors for Sports/Physical Functioning. The only demographic factor that predicted perceived quality of life scores was gender, with girls reporting lower scores in Sports/Physical Functioning, Pain/Comfort, and Global Functioning domains. The Pediatric Outcomes Data Collection Instrument gives discriminatory detailed textured evaluation of the outcome of children treated for skeletal sarcoma. Further development of quality of life measures is needed to allow its use in treatment selection.

SU-FF-T-339: Pediatric Sarcoma Radiotherapy: Target Coverage and Normal Tissue Sparing in 66 Patients Treated with External-Beam Photon Techniques

Purpose: To investigate the variation in target coverage, normal tissue dosimetry, and treatment planning statistics for pediatric sarcoma patients treated with external-beam radiation therapy (EBRT) and develop a baseline for future comparison of new methods and modalities such as proton and intensity-modulated arc therapy. Methods: From January 2003 to July 2005, 66 pediatric patients (1.4–21.6 years old, median 11.6) with soft-tissue and bone sarcomas were prospectively treated on an institutional phase II protocol using EBRT that included forward planned multi-segment 3-dimensional conformal (FPMS-RT) or inverse-planned intensity-modulated radiation therapy (IMRT) with or without low-dose-rate brachytherapy. Results: Beam arrangement consisted of 2-field (11%), multifield coplanar (49%), and noncoplanar (40%). Fields per fraction averaged 7 (2–19) utilizing 6MV (88%) and 6/15MV (12%) photons. MU per fraction averaged 333 (252 for FPMS-RT and 478 for IMRT). PTV ranged from 35 cm3 to 4657 cm3. Total delivered radiation doses ranged from 41.4Gy to 70.2Gy (median, 50.4Gy). Beam delivery time for each fraction (including inter-field beam-off) averaged 9 minutes (5.2 minutes non-IMRT, 17 minutes IMRT with a range of 7–45 minutes). Median PTV D95 and V95 were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the initial phase and 97.8% and 99.2% for a reduced volume phase. The spinal cord dose exceeded 45 Gy and was limited to 52 Gy (<1 c.c.) in 13 out of 36 patients due to tumor involvement or target volume proximity (spinal cord tumors). Conclusions: Improvements in conformity and dose gradient with current methods are still required for challenging paraspinal and head and neck cases. In general, critical organ constraints compromise the delivery of intended high dose to the planned target; however, the inability to achieve CTV coverage (V95>95%) for some patients does not appear to result in significant risk of early local recurrence.

Long-term results of intraoperative presacral electron boost radiotherapy (IOERT) in combination with total mesorectal excision (TME) and chemoradiation in patients with locally advanced rectal cancer

We analyzed the long-term results of patients with locally advanced rectal cancer using a multimodal approach consisting of total mesorectal excision (TME), intraoperative electron-beam radiation therapy (IOERT), and pre- or postoperative chemoradiation (CRT). Between 1991 and 2003, 210 patients with locally advanced rectal cancer (65 International Union Against Cancer [UICC] Stage II, 116 UICC Stage III, and 29 UICC Stage IV cancers) were treated with TME, IOERT, and preoperative or postoperative CHT. A total of 122 patients were treated postoperatively; 88 patients preoperatively. Preoperative or postoperative fluoropyrimidine-based CRT was applied in 93% of these patients. Median age was 61 years (range, 26-81). Median follow-up was 61 months. The 5-year actuarial overall survival (OS), disease-free survival (DFS), local control rate (LC), and distant relapse free survival (DRS) of all patients was 69%, 66%, 93%, and 67%, respectively. Multivariate analysis revealed that UICC stage and resection status were the most important independent prognostic factors for OS, DFS, and DRS. The resection status was the only significant factor for local control. T-stage, tumor localization, type of resection, and type of chemotherapy had no significant impact on OS, DFS, DRS, and LC. Acute and late complications > or =Grade 3 were seen in 17% and 13% of patients, respectively. Multimodality treatment with TME and IOERT boost in combination with moderate dose pre- or postoperative CRT is feasible and results in excellent long-term local control rates in patients with intermediate to high-risk locally advanced rectal cancer.

Prospective evaluation of hepatitis B, C and HIV infections as possible sequelae of antineoplastic treatment in paediatric sarcoma patients: A report from the Late Effects Surveillance System

Cancer therapy and supportive measures entail the risk of infection with hepatitis B (HBV), hepatitis C (HCV) or human immunodeficiency virus (HIV). The objective of this analysis was to establish the incidence of infections with these viruses during antineoplastic treatment in our paediatric sarcoma patients, who are being followed-up within the Late Effects Surveillance System (LESS), which prospectively registers sequelae of therapy for Ewing's-, soft tissue- and osteosarcoma in patients treated in Germany, Austria and Switzerland within the trials EICESS-92/EURO-E.W.I.N.G.-99, CWS-96/CWS-2002P and COSS-96. We studied 264 eligible relapse-free paediatric patients [median age at diagnosis 14.3 (IQR 11.1-16.4) years], treated from January 7, 1998 until April 24, 2004. According to the LESS protocol, serological examinations for HBV, HCV and HIV were scheduled 4 weeks and 6 months after cessation of antineoplastic treatment. The median follow-up was 20.6 (IQR 12.4-26) months. None of the patients was reported to have acquired HBV, HCV or HIV during antineoplastic treatment. Blood donor screening and prophylactic measures employed in Germany, Austria and Switzerland to prevent infections of cancer patients with HBV, HCV and HIV seem to be very effective, having fully prevented new infections in this large cohort of paediatric sarcoma patients.

Prospective longitudinal evaluation of doxorubicin‐induced cardiomyopathy in sarcoma patients: A report of the late effects surveillance system (LESS)

Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland. The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2). In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval. After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.

Thromboembolic events (TEE) in children and young adults with sarcoma

8524 Background: Adults with malignancy are at increased risk for thromboembolic events (TEE). However, data on TEE in pediatric patients with cancer are limited. Methods: To ascertain the risk and clinical features of TEE in pediatric sarcoma patients, we reviewed records on 119 consecutive patients with sarcoma treated from 10/80 to 07/02. Results: Median patient age was 18 years (range 4–32). Twenty-two TEE were diagnosed in 18/119 (15.1%) patients. Incidence by diagnosis was Ewing's sarcoma 7/61 (11.5%), osteogenic sarcoma 2/20 (10%), rhabdomyosarcoma 4/24 (16.7%) and other sarcomas 5/14 (35.7%). TEE developed in 12/51 (23.5%) patients with metastases at presentation vs. 6/68 (8.8%) with local disease (p=0.028). Thromboses were detected at presentation in 13/22 (59.1%), during the initial treatment cycle in 4/22 (18.2%), and at recurrence in 5/22 (22.7%). Ten (45.5%) events were asymptomatic (detected on routine imaging or autopsy). Sites of thromboses were deep veins of the extremities 10/22 (45.5%),...

Thromboembolic events (TEE) in children and young adults with sarcoma

8524 Background: Adults with malignancy are at increased risk for thromboembolic events (TEE). However, data on TEE in pediatric patients with cancer are limited. Methods: To ascertain the risk and clinical features of TEE in pediatric sarcoma patients, we reviewed records on 119 consecutive patients with sarcoma treated from 10/80 to 07/02. Results: Median patient age was 18 years (range 4–32). Twenty-two TEE were diagnosed in 18/119 (15.1%) patients. Incidence by diagnosis was Ewing's sarcoma 7/61 (11.5%), osteogenic sarcoma 2/20 (10%), rhabdomyosarcoma 4/24 (16.7%) and other sarcomas 5/14 (35.7%). TEE developed in 12/51 (23.5%) patients with metastases at presentation vs. 6/68 (8.8%) with local disease (p=0.028). Thromboses were detected at presentation in 13/22 (59.1%), during the initial treatment cycle in 4/22 (18.2%), and at recurrence in 5/22 (22.7%). Ten (45.5%) events were asymptomatic (detected on routine imaging or autopsy). Sites of thromboses were deep veins of the extremities 10/22 (45.5%),...

Development of a clinical-scale method for generation of dendritic cells from PBMC for use in cancer immunotherapy

There is growing interest in the use of dendritic cells (DCs) for treatment of malignancy and infectious disease. Our goal was to develop a clinical scale method to prepare autologous DCs for cancer clinical trials. PBMC were collected from normal donors or cancer patients by automated leukapheresis, purified by counterflow centrifugal elutriation and placed into culture in polystyrene flasks at 1 x 10(6) cells/mL for 5-7 days at 37 degrees C, with 5% CO(2), with IL-4 and GM-CSF. Conditions investigated included media formulation, supplementation with heat in activated allogeneic AB serum or autologous plasma and time to harvest (Day 5 or Day 7). DCs were evaluated for morphology, quantitative yield, viability, phenotype and function, including mixed leukocyte response and recall response to tetanus toxoid and influenza virus. DCs with a typical immature phenotype (CD14-negative, CD1a-positive, mannose receptor-positive, CD80-positive, CD83-negative) were generated most consistently in RPMI 1640 supplemented with 10% allogeneic AB serum or 10% autologous plasma. Cell yield was higher at Day 5 than Day 7, without detectable differences in phenotype or function. In pediatric sarcoma patients, autologous DCs had enhanced function compared with monocytes from which they were generated. In this patient group, starting with 8.0 +/- 3.7 x 10(8) fresh or cryopreserved autologous monocytes, DC yield was 2.1 +/- 1.0 x 10(8) cells, or 29% of the starting monocyte number. In the optimized clinical-scale method, purified peripheral monocytes are cultured for 5 days in flasks at 1 x 10(6) cells/mL in RPMI 1640, 10% allogeneic AB serum or autologous plasma, IL-4 and GM-CSF. This method avoids the use of FBS and results in immature DCs suitable for clinical trials.

Radiation therapy for consolidation of metastatic or recurrent sarcomas in children treated with intensive chemotherapy and stem cell rescue. A feasibility study

Purpose: To assess the role of consolidative radiation therapy (CRT) in conjunction with myeloablative therapy with or without total body irradiation (TBI) in children and young adults with metastatic or recurrent sarcoma.Methods and Materials: Twenty-one pediatric sarcoma patients with metastatic (10) or recurrent (11) disease were entered on a prospective feasibility study of intensive myeloablative therapy with or without TBI. Median patient age was 17.8 years (range, 9.4–24.7 years). Primary histologies included Ewing’s (12), PNET (3), and other soft tissue sarcomas (6). Twenty patients received induction chemotherapy. Myeloablative therapy consisted of TBI in 11 patients with either high dose melphalan/etoposide (9) or high dose cytoxan/thiotepa (2). TBI consisted of 12 Gy in 2 Gy fractions delivered twice daily over 3 days. Ten patients received high dose chemotherapy alone, either with thiotepa/carboplatinum/etoposide (8) or cytoxan/carboplatinum (2). Myeloablative therapy was followed by autologous stem cell rescue (ASCR) 24 to 48 hours after completing chemotherapy. Fourteen patients (67%) received CRT either prior to (5) or following (9) myeloablative therapy. Median CRT dose was 37.2 Gy (range, 20–60). Fifty-one disease sites were present prior to myeloablative therapy. Twelve (24%) were bulky (> 8 cm) and 18 (35%) underwent surgical debulking. The median follow-up of surviving patients was 15 months (range, 8–20) with 25% of patients having been followed for more than 20 months.Results: The 3-year actuarial disease-free (DFS) and overall survival (OS) rates for the entire group were 36% and 27%, respectively. Following myeloablative treatment, responses were: 11 complete, 6 partial, 1 stable, and 3 progressive disease. Sixteen patients (71%) have relapsed. The most common site of relapse was the lung (13). Of the 51 disease sites present prior to myeloablative therapy, 36 sites (71%) were amenable to CRT. Non-amenable sites were: multiple lung metastases (13) and bone marrow (2). Twenty-six amenable sites (51%) received CRT either prior to (14) or following (12) ASCR. Amenable sites treated with CRT had a better 3-year actuarial local control (80 vs 37%) (p = 0.0065) than amenable sites not treated with CRT. Factors associated with improved disease-free survival (DFS) in univariate analysis were induction chemotherapy response (p = 0.002) and extent of surgical resection (p = 0.045). There was a trend toward improved DFS on univariate analysis with the use of TBI as part of myeloablative therapy (p = 0.07). The one factor associated with improved OS on univariate analysis was induction chemotherapy response (p = 0.007). Multivariate analysis revealed that induction chemotherapy response is the only factor that remains significant for DFS (p = 0.032) as well as for OS (p = 0.017). Patients with complete response to induction therapy had 40% probability of survival versus all other patients who had 10% survival (p = 0.05).Conclusion: Consolidative radiotherapy is feasible in primary metastatic or recurrent pediatric sarcoma patients treated with myeloablative therapy with or without TBI. CRT to sites amenable to irradiation provided an improved 3-year actuarial local control than that seen in sites amenable to CRT that did not undergo radiotherapy. There was a trend for improved DFS with the use of TBI. Improved DFS and OS can be predicted by response to induction therapy. This intensive regimen may improve the cure rate of advanced pediatric sarcomas in select patients.

De novo germline mutations of the p53 gene in young children with sarcomas

Germline p53 mutations are associated with cancer predisposition in Li-Fraumeni families as well as in individuals with component tumors of the syndrome. In the majority of cases these mutations have been shown to be inherited rather than de novo. We screened 59 children with primary bone or soft tissue sarcomas. Germline p53 mutations were identified in 2 patients. Interestingly, analysis revealed that both mutations were de novo. Although the frequency of germline p53 mutations in primary pediatric sarcoma patients is low, there is evidence for the importance of considering pediatric patients for testing for de novo mutations.

Problems and controversies in the management of childhood sarcomas.

Multidisciplinary care and advances in chemotherapy have dramatically improved the prognosis of paediatric sarcoma patients, but much work remains. There are new techniques for molecular diagnosis of Ewing's sarcomas and alveolar rhabdomyosarcomas, with molecular techniques of staging and subclassification under development. Osteosarcoma is a clinically heterogeneous disease which continues to resist biologic diagnosis, classification, or staging. In chemotherapy, the roles of ifosfamide and doxorubicin in rhabdomyosarcoma treatment remain unclear. While many children with metastatic or recurrent sarcomas undergo massive therapy with peripheral stem cell or autologous marrow rescue, the efficacy of these manoeuvres is debatable. Osteosarcoma appears to respond best to regimens containing doxorubicin and cisplatin, while the roles of alkylating agents, high-dose methotrexate, and carboplatin remain unclear. Ewing's sarcoma treatment increasingly includes surgery because of the risk of secondary osteosarcoma after radiation. Most osteosarcoma patients now have limb-sparing excisions, though amputation may provide better function and cosmesis with less risk of complications in some patients. The role of multimodal treatment including chemotherapy for the miscellaneous soft tissue sarcomas remains uncertain.

Randomized trial of recombinant human granulocyte-macrophage colony-stimulating factor in pediatric patients receiving intensive myelosuppressive chemotherapy.

To evaluate whether recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicities and supportive care requirements of an intensive combination chemoradiotherapy regimen in pediatric and young adult sarcoma patients. Thirty-seven newly diagnosed patients age 1 to 25 years were randomized to receive 18 cycles of chemotherapy alone or with GM-CSF beginning in cycle 3. GM-CSF (5 to 15 micrograms/kg/d subcutaneously) was begun 24 hours after the completion of chemotherapy and continued through day 19 of each cycle or until the absolute granulocyte count (AGC) was > or = 500/microliter on 2 consecutive days. GM-CSF reduced the median duration of grade 4 granulocytopenia from 9.0 days (range, 2 to 24) to 7.0 days (range, 1 to 21) (P < .0001), but did not significantly affect the grade of granulocyte nadir. No differences were seen in the incidence or types of infectious complications, incidence or duration of hospitalization and antimicrobial therapy, response to chemotherapy, or event-free or overall survival. GM-CSF was associated with more severe and protracted thrombocytopenia (median platelet nadir, 29,500/microliter [range, 3,000 to 288,000] v 59,000/microliter [range, 3,000 to 309,000], P < .0001; median time to recovery > 75,000/microliter, 16.0 days [range, 0 to 61] v 14.0 days [range, 0 to 38], P < .0001). GM-CSF does not produce clinically meaningful reductions in the degree or duration of severe granulocytopenia following intensive multiagent chemotherapy, but is associated with worsened thrombocytopenia. GM-CSF also does not reduce the need for hospitalization or the incidence of febrile neutropenia and infectious complications. We conclude that the costs and increased toxicities associated with the use of this agent are not justified by its minimal clinical benefit for regimens of this level of intensity.

Cardiotoxicity and cardioprotection during chemotherapy

Chemotherapy drugs have been reported to cause cardiac side effects including cardiomyopathy, ischemia, arrhythmias, and myocardial necrosis. Most important in terms of daily practice is anthracycline-induced cardiomyopathy. The bisdioxopiperazine compound, dexrazoxane (ICRF-187, ADR-529), has been shown to prevent this cumulative side effect of the anthracyclines. Recent randomized trials performed in breast cancer and in pediatric sarcoma patients have demonstrated the efficacy of this approach, which permits the administration of anthracyclines to greater cumulative doses and thus leads to a substantial reduction in the incidence of decreased left-ventricular ejection fraction or congestive heart failure. Response rates were not significantly different with the use of dexrazoxane in these trials. The risk ratio for a cardiac event was decreased by two to threefold in randomized breast studies involving more than 700 women. Paclitaxel also has been reported to cause arrhythmias and possibly ischemia. In a large data base, National Cancer Institute investigators found a 0.29% incidence of grade 4 or 5 cardiac toxicities, including heart block, ventricular tachycardia, and ischemic events. Other important chemotherapy-related cardiac toxicities discussed include fluorouracil-induced angina and arrhythmias, interleukin-4 induced-cardiomyopathy, and cardiotoxicity associated with autologous bone marrow transplantation procedures.