Mitoxantrone, 5-fu,and leucovorin in breast cancer

Eighteen patients (17 evaluable for response) with metastatic breast cancer were treated with mitoxantrone 10 mg/m² day 1, followed by 5-fluorouracil 375 mg/m² day 1-5, and high-dose leucovorin 500 mg/m² day 1-5 given every 28 days. There was one complete and four partial responses for an objective response rate of 30% and 41% stable disease. The major toxicities were hematologic and gastrointestinal. This regimen has activity in metastatic breast cancer comparable to conventional and/or standard chemotherapy regimens for advanced disease. © 1994 Wiley-Liss, Inc.     

Single-Agent Ifosfamide in Patients with Recurrent Neuroblastoma (Ensg Study 2)

Twenty-five patients with progressive or recurrent neuroblastoma were treated with single-agent ifosfamide. In 2 of 10 relapsing patients, an objective response was observed. If ifosfamide is administered in a dose of 3000 mg/m² for 2 days every 3 weeks, a response can be expected in 8% of the cases.     

Hepatic artery infusion with 5-fluorouracil and mitomycin-C in metastatic colorectal carcinoma phase II study

Thirty-two patients with hepatic metastases colorectal carcinoma were treated with hepatic artery infusion (HAI) employing 5-fluorouracil (5-FU) and mitomycin-C (mito-C). Catheters were placed percutaneously via the femoral artery. Two schedules were employed: (I) 5-FU 1,200 mg/m2 IA (D1-4) and mito-C 8 mg/m2 IA (D1 + D4); (2) 5-FU 1,200 mg/m2 IA (D1-6) and mito-C 8 mg/m2 IA (D1 + D4). Courses were repeated every 4 weeks. Thirty patients with measurable disease were evaluable, 22 received schedule I and 8 patients schedule II. Complete response occurred in two patients (6.7%) and partial response in 13 patients (43.3%). Five patients (16.7%) had minimal regression. The overall response rate as 66.7%. Median survival of all patients from start of treatment was 11.2 months. Median survival of responders and nonresponders was 12.4 months and 4.6 months, respectively (P less than 0.05). No differences in response rates, duration of response, or survival was seen between the two schedules. Drug toxicity was moderate to severe, but morbidity of HAI per se was minimal. Intermittent HAI of 5-FU and mito-C is a well-tolerated treatment modality associated with few serious complications. The response rate, duration of response, and the survival is comparable to continuous HAI infusion of 5-FU or floxuridine (FUDR). As given in this study, mito-C did not appear to provide added benefit.     

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

BACKGROUND: Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion. PROCEDURE: We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial. RESULTS: Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home. CONCLUSIONS: Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity.     

Interstitial pneumonitis probably induced by cyclophosphamide in nephrosis

A case of interstitial shadows associated with oral cyclophosphamide therapy in a 32-month-old girl with steroid-resistant nephrotic syndrome, who was admitted to the Nishi-Kobe Medical Center with systemic edema, is reported. Due to the lack of response to prednisolone, cyclophosphamide was also administered orally at a dose of 3 mg/kg per day, 4 weeks after the start of steroid therapy. Approximately 3 weeks after the combination treatment she developed a fever, dry cough and cyanosis. Radiographic examination showed diffuse ground-glass shadow in both lungs, presumably indicating that she had interstitial pneumonitis. Her pulmonary signs and symptoms deteriorated despite various antimicrobial treatments. A discontinuation of cyclophosphamide and the administration of high-dose methylprednisolone yielded a dramatic improvement. These findings suggest that the diffuse pulmonary disease in this case was induced by cyclophosphamide. Since interstitial pneumonitis may be fatal and irreversible, attention should be paid to this rare complication even in patients undergoing low-dose oral cyclophosphamide treatment.     

Treatment of advanced head and neck cancer by means of radiation therapy plus chemotherapy — a randomised trial

Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy. The distribution of tumour types and stages was similar in the two treatment groups. The response rates to radiation therapy alone (50% complete plus partial response) and to radiation therapy plus chemotherapy (60% complete plus partial response) were not significantly different. However, a significant difference in survival was found between the two groups. The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks; that for the combined therapy was 36 weeks. The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial.     

Economic evaluation of recombinant human granulocyte colony-stimulating factor in very high-risk childhood acute lymphoblastic leukemia

PURPOSE: In a previous randomized study, the authors reported that granulocyte colony-stimulating factor (G-CSF) increased the chemotherapy dose-intensity delivered during the consolidation therapy of high-risk childhood acute lymphoblastic leukemia (ALL). The aim of the current study was to perform an economic evaluation in the same cohort. METHODS: In this open-label multicenter randomized trial, prophylactic G-CSF was administered after consolidation therapy courses. Economic data were retrospectively quantified for each patient: hospital stays, drugs, and blood products. RESULTS: Sixty-seven children were enrolled in the very high-risk branch of the FRALLE 93 protocol. Chemotherapy dose-intensity was significantly increased (105 +/- 5% in the G-CSF group vs. 91 +/- 4% in the non-G-CSF group, P < 0.001). The mean total costs per child were not statistically different: 32,309 dollars in the G-CSF group versus 31,569 dollars in the non-G-CSF group. Further analysis per child and per course (R3 or COPADM) demonstrated that the mean cost of hospitalization and the mean cost of intravenous antibiotics were significantly decreased in the G-CSF group after R3 courses (3,857 dollars vs. 4,993.80 dollars, P < 0.001; 171.40 dollars vs. 306.20 dollars, P = 0.029, respectively), but the cost of platelet transfusion was significantly increased (P = 0.03). Conversely, post-COPADM costs were similar. Finally, mean costs per course in the two randomized groups were not significantly different: 5,848.80 dollars versus 6,181 dollars and 7,388.10 dollars versus 6,475.70 dollars for R3 and COPADM, respectively. The 3-year probability of event-free survival between the two groups was not different. CONCLUSIONS: G-CSF can increase chemotherapy dose-intensity in very high-risk ALL without raising costs, but event-free survival was not improved. The cost benefit of prophylactic treatment by G-CSF relies on the chemotherapeutic regimen given prior to G-CSF administration.     

Treatment of advanced head and neck cancer by means of radiation therapy plus chemotherapy--a randomised trial.

Fifty-eight patients with advanced head and neck cancer were entered into a randomised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy. The distribution of tumour types and stages was similar in the two treatment groups. The response rates to radiation therapy alone (50% complete plus parital response) and to radiation therapy plus chemotherapy (60% complete plus partial response) were not significantly different. However, a significant difference in survival was found between the two groups. The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks; that for the combined therapy was 36 weeks. The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial.     

Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide

PURPOSE: Standard multiagent chemotherapy for osteosarcoma may include platinum compounds, doxorubicin, and high-dose methotrexate. By identifying new chemotherapeutic strategies, the outcome of these patients can be improved and the toxicity of treatment regimens decreased. PATIENTS AND METHODS: The authors evaluated the activity of the combination of cyclophosphamide (500 mg/m2 per day for 5 days) and etoposide (100 mg/m2 per day for 5 days) given with granulocyte colony-stimulating factor (G-CSF) to children with osteosarcoma unresponsive to conventional treatment. RESULTS: Fourteen patients with refractory osteosarcoma were treated with this combination. Twelve patients had been previously treated with a multiagent regimen that included carboplatin, ifosfamide, methotrexate, and doxorubicin. Seven of 11 evaluable patients had a poor histologic response in their primary tumor at the time of definitive surgery (Huvos grade 1 or 2). Sites of relapse included lung, bone, and brain. A total of 47 courses were given. An overall response rate of 28.5% was achieved. A complete response was obtained in one patient (7.1%), a partial response was obtained in three patients (21.4%), and stable disease for 1 to 4 months was achieved in five patients (35.7%). Five patients (35.7%) had progressive disease. Grade 4 neutropenia was the primary form of toxicity observed; the median duration of absolute neurophil count less than 500/microL was 4 days. CONCLUSIONS: The combination of cyclophosphamide and etoposide resulted in a response rate of 28.5% in patients with refractory or relapsed osteosarcoma, and its incorporation into front-line therapies deserves further evaluation.     

Treatment of stage III neuroblastoma with emphasis on intensive induction chemotherapy: A report from the neuroblastoma group of the spanish society of pediatric oncology

From October 87 to April 92, 172 children were admitted in the N-I-87 protocol of the Spanish Society of Pediatric Oncology for the diagnosis and treatment of neuroblastoma. Forty-eight were considered Evans stage III, 33 of them being older than 1 year. All children were treated with induction chemotherapy (IC) and surgery. IC consisted of three courses of high-dose cisplatin-VM-26 alternating with three further courses of cyclophosphamide-doxorubicin (CAD). Infants less than 1 year received the same drugs at lower doses. After surgery, maintenance chemotherapy was administered to all children during 14 months. It consisted of four pairs of drugs rotated every 4 weeks. Radiotherapy was administered exclusively to patients older than 1 year with residual tumor after IC and surgery. Response was evaluated after IC and surgery. In children older than 1 year, response was obtained in 28/33 (88%). Fifteen of them (47%) achieved complete remission (CR), seven (22%) good partial response (GPR), six (19%) partial response (PR); and in three patients (9%) there was progressive disease (PD). Actuarial survival at 48 months was 0.60 ± 0.10 and EFS was 0.61 ± 0.12. Audiologic impairment was considered the worst toxicity. In children less than 1 year the response rate to IC and surgery was 93% (14/15); nine infants obtained complete response and four had GPR. Only one patient experienced PD in the first 6 months of therapy and died. The other 14 are alive and well at a mean follow-up time of 48 months. Chemotherapy toxicity was mild and reversible. © 1995 Wiley-Liss, Inc.     

Suppression of adrenal function in children with acute lymphoblastic leukemia following induction therapy with corticosteroid and other cytotoxic agents

OBJECTIVE: To evaluate adrenal function in children with acute lymphoblastic leukemia (ALL) after induction therapy with corticosteroid and other cytotoxic agents.Study design Children with ALL (N=24) were treated with prednisolone (40 mg/m(2) per day) for 28 days during the induction phase followed by 1 week of oral dexamethasone every 4 weeks. A low-dose (1 microg) adrenocorticotropin (ACTH) test was performed 2 weeks after discontinuation of prednisolone; it was repeated 2 weeks later and then every 4 weeks in patients with adrenal suppression until normal response was achieved. RESULTS: Adrenal suppression was found in 46% of patients at 2 weeks after discontinuation of prednisolone; it persisted in 38%, 29%, and 13% of patients through 4 weeks, 8 weeks, and 20 weeks, respectively. Adrenal suppression appeared to last significantly longer in children aged >or=5 years than in children aged <5 years. Four children developed febrile neutropenia; all belonged to the adrenal suppressed group and were unable to mount an adequate adrenal response to the stress. CONCLUSIONS: About 50% of children with ALL developed adrenal suppression 2 weeks after a 4-week induction therapy with prednisolone. The suppression could persist through 20 weeks and may hinder an adequate adrenal response during acute febrile illness.     

Phase II study of ifosfamide in childhood brain tumors: A report by the French society of pediatric oncology (SFOP)

Forty-two evaluable pediatric patients with a variety of recurrent primary brain tumors participated in a phase II ifosfamide trial. Their mean age was 10 years. All patients were treated with ifosfamide, 3 g/m²/day for 2 days every 2 weeks. Response was assessed on clinical and radiological criteria after at least 2 courses of therapy. The overall response rate was 12% (5/42). One complete and 2 partial responses were documented in 21 patients with medulloblastoma. A partial response was demonstrated in 1 patient with primitive neurectodermal tumor (PNET) and in 1 patient with ependymoma. No activity was observed in astrocytic tumors. Toxicity was primarily neurologic (16 out of 54 patients, 30%). Hematological toxicity, without severe morbidity, was encountered in 9% of courses (16/179). Ifosfamide, administered at this dose regimen has modest efficacy in the treatment of recurrent childhood medulloblastoma and ependymoma and appears inactive for gliomas. Further trials with other dose schedules are necessary to assess the activity of this drug. However, according to the neurotoxicity observed in our trial, we would not recommend building a protocol using ifosfamide for highly progressive brain tumors. © 1993 Wiley-Liss, Inc.     

Use of granulocyte colony stimulating factor to reduce the toxicity of super-VAC chemotherapy in advanced solid tumours in childhood

Children with advanced solid tumours at the Royal Alexandra Hospital for Children (RAHC) receive an intensive four drug chemotherapy combination, Super-VAC (cyclophosphamide, 500 mg/m², adriamycin, 30 mg/m², actinomycin-D, 0.5 mg/m², all daily for 3 days, and vincristine, 1.5 mg/m² weekly). The majority of patients respond well to three courses of such therapy, but with considerable morbidity, including fever, neutropenia, and mucositis. In an attempt to reduce the morbidity of Super-VAC, G-CSF was added. We documented various parameters in 12 patients who received 28 cycles with G-CSF and compared them to an historical control group of 37 cycles in the preceding 14 patients who received Super-VAC. The median duration of each cycle was 23 days with G-CSF and 28 days without G-CSF (P = 0.004). However, differences in requirements for inpatient care (median 16 v. 20 days), intravenous antibiotics (median 9 v. 10 days), amphotericin (median 5 v. 3 days), morphine (median 8.5 v. 7 days), or TPN (median 6.5 v. 8 days) did not reach statistical significance. As expected, a significant difference in neutrophil recovery was demonstrated between the two groups (median 11 v. 16 days, P < 0.0001) but not in platelet recovery (median 13 v. 13 days). The use of G-CSF with Super-VAC resulted in a shorter cycle length, so increasing the dose intensity. A reduction in morbidity could not be demonstrated. No toxic side effects from G-CSF were noted. © 1995 Wiley-Liss, Inc.     

Outcome of high-risk neuroblastoma using a dose intensity approach: improvement in initial but not in long-term results.

BACKGROUND: Stage 4 and MYCN amplified (MNA) neuroblastoma in children have a poor prognosis. Our aim was to increase initial and long-term response in this population. PROCEDURE: High-risk children were studied according to the International Neuroblastoma Staging System, then treated with high-dose cyclophosphamide and high-dose carboplatin, followed by surgery and autologous stem cell transplant or maintenance chemotherapy. RESULTS: From June 1992 to December 1998, 83 children were admitted in the study (72 stage 4> 1 year, 5 stage 4 MNA infants, and 6 MNA stage 3 children); tumor tissue was obtained from 73, MYCN was performed in 65, being amplified in 21 (32%). Induction chemotherapy was administered in the expected time in 35% of patients. Its toxicity was mainly hematologic followed by infections, and there were 3 chemotherapy-related deaths. Delayed surgery was performed on 60 patients with complete or >90% resection in 80% of cases. Chemotherapy plus surgery produced some response in 90% of patients, 53% were in CR/VGPR; 49 children received autologous SCT, and 16 received maintenance chemotherapy for 9 months. Follow-up ranges are 1-87 months, mean 30 months. S and EFS at 4 years are 0.33 (SD 0.02). CONCLUSIONS: High-dose cyclophosphamide and high-dose carboplatin are effective in the initial treatment of neuroblastoma; combined with surgery they produce some response in most patients. Nevertheless, the CR/VGPR rate reaches only 53%. Survival time has also been prolonged but most patients relapse with metastases.     

Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report

PURPOSE: The objectives of this study were: 1) to compare the time to hematologic recovery (absolute neutrophil count [ANC] > or = 1,000/mm3 and platelet count > or = 100,000/mm3) in a randomized prospective study of two doses of granulocyte colony-stimulating factor (G-CSF) (5.0 vs. 10.0 microg/kg per day) after ifosfamide, carboplatin, and etoposide (ICE) chemotherapy; and 2) to determine the response rate (complete response [CR] + partial response [PR]) of ICE in children with refractory or recurrent solid tumors. PATIENTS AND METHODS: From June 1992 until November 1994, 123 patients with recurrent or refractory pediatric solid tumors were treated with ifosfamide (1,800 mg/m2 per day x 5), carboplatin (400 mg/m2 per day x 2), and etoposide (100 mg/m2 per day x 5) and randomized to receive either 5.0 microg/kg per day or 10.0 microg/kg per day of G-CSF subcutaneously until recovery of ANC to > or = 1,000/mm3. RESULTS: The incidence of grade 4 neutropenia during the first course was 88%. Median time from the start of chemotherapy to ANC > or = 1,000/mm(-3) for all patients during courses 1 and 2 was 21 and 19 days, respectively. The incidence of developing platelet count < or = 20,000/mm3 during course 1 was 82%. The median time from the start of the course of chemotherapy to platelet recovery > or =100,000/mm3 for all patients during courses 1 and 2 was 27 days. There was no significant difference in the median time of ANC recovery, platelet recovery, or incidence of grade 4 neutropenia; and in the median days of fever and the incidence of infections requiring hospitalization and intravenous antibiotics during courses 1 and 2, there was no significant difference between the two doses of G-CSF. One hundred eighteen patients were evaluated for response to ICE. The overall response rate (CR + PR) in this study was 51% (90% confidence interval, 43%-59%). The CR rate for all diagnostic categories was 27%. The Kaplan-Meier estimates of 1-year and 2-year survival probabilities for all patients were 52% and 30%, respectively. CONCLUSION: In summary, this combination of chemotherapy (ICE) was associated with a high CR rate (27%) in children with recurrent or refractory solid tumors, but also with a high incidence of grade 4 neutropenia and thrombocytopenia. Doubling the dose of G-CSF from 5.0 to 10.0 microg/kg per day after ICE chemotherapy did not result in an enhancement of neutrophil or platelet recovery or the incidence of grade 4 neutropenia developing.     

Granulocyte-colony-stimulating factor after allogeneic and autologous bone marrow transplantation in children

We evaluated the use of granulocyte CSF (G-CSF) after both allogeneic BMT (allo-BMT) and autologous BMT (ABMT) in children. After allo-BMT, G-CSF was used in 15 children who were compared with 20 historical controls. The ABMT patients were two sequential groups: the G-CSF group of 13 children and 11 historical controls. The patients were conditioned with different high-dose chemotherapy regimens with or without total body irradiation. G-CSF was administered at 5 μg/kg/day s.c. and was continued until an absolute neutrophil count (ANC) of 1,000 × 10⁶/l was reached. Following allo-BMT, G-CSF accelerated myeloid engraftment with a difference of 5 days at the ANC level of 500 × 10⁶/l (P < 0.02) and 9 days at 1,000 × 10⁶/l (P < 0.001). In the ABMT patients, G-CSF also accelerated myeloid engraftment. The difference between the G-CSF group and the control group was 6 days at ANC 200 (P < 0.05), 11 days at ANC 500 (P < 0.02), and 17 days at ANC 1,000 (P < 0.005). In the ABMT patients, benefit by G-CSF was also observed in a smaller number of days with fever and days on antibiotics. We conclude that G-CSG significantly accelerated myeloid engraftment, after both allogeneic and autologous BMT in children, and also decreased the duration of febrile illness in the ABMT patients. © 1996 Wiley-Liss, Inc.     

Randomized study for the treatment of adult advanced Hodgkin's disease: Epirubicin,vinblastine, bleomycin,and dacarbazine (EVBD) versus mitoxantrone,vinblastine, bleomycin,and dacarbazine (MVBD)

Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens ahowed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We feld that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease. © 1994 Wiley-Liss, Inc.     

Chlorozotocin treatment of advanced gastrointestinal cancer

From April 1981 to December 1981, 34 consecutive patients with advanced gastrointestinal cancer were treated with chlorozotocin at the dosage of 40 mg/m2 daily for 5 consecutive days (30 mg/m2 in patients pretreated with chemotherapy) every 6 weeks. In the 30 patients evaluable for response, a 3.3% objective response rate was encountered. Toxicity was not significant and consisted mainly in reversible myelosuppression. Median survival was 3 months. At the dosage and schedule used, chlorozotocin does not seem to be an effective agent in the treatment of advanced gastrointestinal cancer.     

Efficacy of Recombinant Human Granulocyte Colony-Stimulating Factor and Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Neutropenic Children with Malignancies

The difference between the effects of administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was studied in 39 children with neutropenia secondary to chemotherapy (absolute neutrophil count (ANC) less than 1,500/μL). The children were divided into two groups. The first group (G-CSF) included 25 children (12 with acute lymphoblastic leukemia [ALL]-non-Hodgkin's lymphoma [NHL] and 13 with solid tumors) and the second group (GM-CSF) included 14 children (5 with ALL-NHL and 9 with solid tumors). All 39 children received of either G-CSF or GM-CSF (5 μg/kg/day) subcutaneously at the end of each chemotherapy course for a maximum duration of 14 days. The effect of G-CSF and GM-CSF on the ANC, the antibiotic therapy administration, and the length of hospital stay were studied for both groups at two cycles of chemotherapy. During both cycles a faster rise of ANC was observed in the children of the first group (G-CSF) compared with those of the second group (GM-CSF), but there was no difference in either the incidence of antibiotic therapy administration between the two groups (26% vs 25%) or the length of hospitalization. Both growth factors were well tolerated by all children studied with minimal side effects observed (including bone pain with G-CSF in 2 of 25 children and pruritus with GM-CSF in 1 of 14). We conclude that G-CSF reduces the duration of neutropenia more than does GM-CSF, but the incidence of severe infection and the duration of hospitalization do not differ between children receiving either G-CSF or GM-CSF.     

Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial

PURPOSE: Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy. PATIENTS AND METHODS: Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. RESULTS: One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases. CONCLUSIONS: Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.