Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. The Intergroup Rhabdomyosarcoma Study-I. A final report. Comparison of long-term outcome of children and adolescents with disseminated non-lymphoblastic non-Hodgkin lymphoma treated with COMP or daunomycin-COMP: A report from the Children's Cancer Group. Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study. Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. Fractionated cylophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (SNCCL): a randomized trial of the Pediatric Oncology Group.
The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma.
                Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered.
                Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years.
                Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma. The results of treatment of 686, previously untreated patients younger than 21 years with rhabdomyosarcoma or undifferentiated sarcoma, who were entered on Intergroup Rhabdomyosarcoma Study-I (IRS-I) were analyzed after a minimum potential follow-up time of 7 years. Patients in Clinical Group I (localized disease, completely resected) were randomized to receive either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC + radiation. At 5 years, approximately 80% of patients given either treatment were still disease-free and there was no significant difference between treatments in the overall percentages of patients surviving of 93% and 81%, respectively (P = 0.67). Patients in Clinical Group II (regional disease, grossly resected) were randomized to receive either vincristine and dactinomycin (VA) + radiation or VAC + radiation. At 5 years, 72% and 65% of the patients, respectively, were disease-free and there was no evidence of a difference between treatments (P = 0.46). The overall survival percentage at 5 years was approximately 72% for both treatments. Patients in Clinical Groups III (gross residual disease after surgery) and IV (metastatic disease) were randomized to receive either "pulse" VAC + radiation or "pulse" VAC + Adriamycin (doxorubicin) + radiation. The complete remission (CR) rate was 69% in Clinical Group III and 50% in IV, with no statistically significant difference in CR rates between treatments in either group. Those who achieved a CR had a nearly 60% chance of staying in remission for 5 years in Clinical Group III compared with approximately 30% in Clinical Group IV. The overall survival percentage at 5 years was 52% in Clinical Group III compared to 20% in Clinical Group IV (P less than 0.0001). The 5-year survival percentage for the entire cohort of 686 patients was 55%. Survival after relapse was poor, being 32% at 1 year and 17% at 2 years. The risk of distant metastasis was much greater than the risk of local recurrence within each clinical group, and there was no evidence of differing types of relapses between treatments. Primary tumors of the orbit and genitourinary tract carried the best prognosis, whereas tumors of the retroperitoneum had the worst prognosis. The authors conclude that for the therapeutic regimens evaluated there was no therapeutic advantage to including radiation in the treatment of Clinical Group I disease, or cyclophosphamide given as a daily low-dose oral regimen in the treatment of Clinical Group II disease or Adriamycin in the treatment of Clinical Groups III and IV diseases. Early Children's Cancer Group (CCG) trials indicated that the cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) regimen was superior to the LSA2L2 regimen for non-lymphoblastic (NLB) non-Hodgkin lymphoma (NHL). Studies by other groups suggested that addition of anthracyclines to standard therapies could improve outcome. Therefore, in 1983 CCG initiated study CCG-503, a randomized trial of COMP vs. daunomycin-COMP (D-COMP) in children and adolescents with disseminated NLB NHL.
                Between December 1983 and April 1990, 404 eligible patients were entered. Patients without central nervous system (CNS) or marrow involvement were randomized to receive COMP (N = 139) or D-COMP (N = 145). Randomization was stratified by histology and site of disease. Patients with CNS or marrow involvement (stage IV) were non-randomly treated with D-COMP (N = 120).
                Ten-year event-free survival in COMP and D-COMP patients was similar: 55 +/- 4.3% (Estimate +/- SE) vs. 57 +/- 4.2% (not significant). Stage I-III patients with large-cell (LC) NHL had worse 10-year event-free survival (EFS) (48 +/- 4.9%) than those with small non-cleaved cell (SNCC) NHL disease (61 +/- 3.5%, P < 0.05 in multivariate analysis), but equivalent survival (65 +/- 4.7% vs. 63 +/- 3.5%) due to significantly higher salvage rates in LC patients, especially those failing more than 12 months from diagnosis. Ten-year EFS in stage IV patients was 39 +/- 5.2%. Addition of daunomycin resulted in higher rates of grade 3/4 hematologic toxicity and stomatitis, as well as late cardiac-related deaths. The incidence of second malignant neoplasms was 1.0% at 10 years.
                Addition of daunomycin to standard COMP therapy did not improve outcome in pediatric disseminated NLB NHL. Patients with LC disease had a significantly reduced long-term EFS, but were retrieved at a higher rate than patients with SNCC disease, resulting in equivalent long-term survival.
                Copyright 2001 Wiley-Liss, Inc. Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy. A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable). We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS).
                Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy.
                From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or "RMS-like" tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome.
                Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors.
                (c) 2008 Wiley-Liss, Inc. We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).
                High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.
                Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar.
                The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use. We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity.
                Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies.
                In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004).
                DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment. The Pediatric Oncology Group (POG) conducted a two-arm, randomized study for the treatment of children and adolescents with stage III small, non-cleaved cell lymphoma (SNCCL). Regimen A, based on the group's previous best treatment for this group of patients, included cyclophosphamide (CTX) and high-dose methotrexate (MTX), as well as vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemoprophylaxis. Regimen B, based on a single institution pilot study (Total B therapy), consisted of two rapidly alternating chemotherapy combinations (CTX, VCR, doxorubicin; MTX, and cytarabine (Ara-C) plus coordinated IT chemotherapy.
                One hundred thirty-four consecutive patients were entered on this study. Seventy patients were randomized to Regimen A, and 64 patients to Regimen B. One hundred and twenty-two patients are eligible for response.
                Complete remission (CR) was achieved by 81% (52/64) of patients on Regimen A, and 95% (55/58) of patients on Regimen B (p=0.014 one-sided). The two-year event-free survival (EFS) is 64% (SE=6%) on Regimen A, and 79% (SE=6%) on Regimen B (p=0.027 by one-sided logrank test). No patient has relapsed on either regimen after a year from diagnosis, although one patient had a second malignancy at day 371. Severe, but manageable, hematologic toxicity was seen in the majority of patients on both regimens, but was more frequent on Regimen B.
                We conclude that the cure rate in stage III SNCCL is significantly improved with the use of a short, six-month chemotherapy regimen of fractionated CTX alternated with coordinated MTX and Ara-C. Results suggest that drug schedule, not simple drug selection, influences outcome.
At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, "no evidence of effect", as identified in this review, is not the same as "evidence of no effect". For Wilms' tumour, rhabdomyosarcoma/undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma and hepatoblastoma only one RCT was available and, therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore, no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours.