PURPOSE To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Increasing numbers of young adults are survivors of childhood cancer [1]. As survival rates have improved for many malignancies, attention has increasingly been focused on the long-term side effects of therapeutic regimens. An important example is gonadal toxicity, a well-known side effect of alkylating agents [1–9]. Although men seem to be more vulnerable than women to this toxicity, premature ovarian failure and infertility are not infrequent among female cancer survivors who have been treated with alkylating agents [1,5,7,8,10,11]. Many of the alkylating agents (such as cyclophosphamide, busulfan, and nitrogen mustard) are known to cause gonadal damage, but little has been reported about the association between ifosfamide long-term ovarian or testicular toxicity [12]. Within our practice, we have seen three cases of POF in young women who had received ifosfamide for treatment of osteosarcoma, raising the possibility that this agent may have caused the gonadal toxicity. The three young women all received chemotherapy and underwent surgical resection of their primary tumors. Ifosfamide was administered under either open protocols or per individualized treatment plans.

BACKGROUND. Recurrent osteosarcoma is a drug-resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET-743) as a salvage therapy in these patients.METHODS. Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET-743 was administered at a dose of 1500 mug/m(2) as a 24-hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle.RESULTS. Twenty-five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12-67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty-one cycles were administered (median number of cycles per patient was 2; range, 1-9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 +/- 29.3 ng X hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 +/- 17.2 ng X hr/mL [n = 12]) or Grade 1-2 (52.6 +/- 15.6 ng X hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response.CONCLUSIONS. ET-743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET-743 with cisplatin or doxorubicin should be considered.

PURPOSE:Successful therapeutic interventions to prevent disease progression in patients with nonmetastatic osteosarcoma have included surgery with adjuvant chemotherapy. Presurgical chemotherapy has been advocated for these patients because of putative improvement in event-free survival (EFS). The advantages of presurgical chemotherapy include early administration of systemic chemotherapy, shrinkage of primary tumor, and pathologic identification of risk groups. The theoretic disadvantage is that it exposes a large tumor burden to marginally effective chemotherapy. The contribution of chemotherapy and surgery timing has not been tested rigorously.PATIENTS AND METHODS:Between 1986 and 1993, we conducted a prospective trial in patients with nonmetastatic osteosarcoma who were assigned randomly to immediate surgery or presurgical chemotherapy. Except for the timing of surgery (week 0 or 10), patients received 44 weeks of identical combination chemotherapy that included high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide, and dactinomycin.RESULTS:One hundred six patients were enrolled onto this study. Six were excluded from analysis. Of the remaining 100 patients, 45 were randomly assigned to immediate chemotherapy, and 55 were randomly assigned to immediate surgery. Sixty-seven patients remain disease-free. At 5 years, the projected EFS +/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61% +/- 8% for presurgical chemotherapy; P =.8). The treatment arms had similar incidence of limb salvage (55% for immediate surgery and 50% for presurgical chemotherapy).CONCLUSION:Chemotherapy was effective in both treatment groups. There was no advantage in EFS for patients given presurgical chemotherapy.

PURPOSE: The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma. PATIENTS AND METHODS: Eligible patients received infusions of 100 mg/m2 per day of etoposide and 3.5 g/m2 per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor. RESULTS: Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% ± 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% ± 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% ± 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi’s syndrome was observed in five patients. CONCLUSION: The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.

A comprehensive multidisciplinary approach has transformed osteosarcoma from a disease with a modest long-term survival to one in which at least two-thirds of patients will be cured. Surgery remains the vital modality for treating the primary tumor, whereas adjuvant chemotherapy plays an essential role in the control of subclinical metastatic disease. Complete surgical excision of the primary tumor remains an essential element of treatment. For many patients, a combination of advances in surgical technique, improved imaging modalities to accurately document tumor extent, and the effect of neoadjuvant chemotherapy has made limb salvage procedures a safe alternative to amputation. In some patients for whom complete surgical excision is impossible, the addition of radiation therapy may allow local tumor control. The most effective chemotherapy agents currently in use include high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide/etoposide. The optimal schedule of therapy is still being investigated, as is the role of dose intensification. Unfortunately, some groups of patients remain at high risk of eventual relapse. Those whose tumors show relatively low degrees of necrosis after administration of chemotherapy have poorer survival than patients with more chemotherapy-responsive tumors. Similarly, patients who present with overt metastatic disease (particularly bone metastases), as well as patients with tumors that recur after treatment, continue to have an unsatisfactory outcome. These groups, in particular, may benefit from future investigations into novel agents, such as biological response modifiers, antiangiogenesis factors, and growth receptor modulation.

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/m(2) 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.

PURPOSE:To estimate the duration of survival (S) of patients with metastatic osteosarcoma (MOS) at diagnosis treated with a multiagent, ifosfamide-containing chemotherapeutic and surgical regimen and to evaluate the toxicity of this regimen.PATIENTS AND METHODS:Thirty patients aged younger than 30 years received two courses of ifosfamide followed by surgery on the primary tumor and metastatic sites. Patients then received a postsurgical multiagent chemotherapeutic regimen that consisted of high-dose methotrexate (HDMTX), ifosfamide, doxorubicin, and cisplatin.RESULTS:The 5-year event-free survival (EFS) rate was 46.7% (95% confidence interval [CI]; 28.5 to 64.9) and 5-year S rate was 53.3% (95% CI; 35.1 to 71.5). Three patients with bone metastases and one patient with lymph node metastases died. Twenty-six patients presented with pulmonary metastatic nodules only. Eight of these patients had at least eight nodules at diagnosis and had an estimated 5-year EFS rate of 25.0% compared with 66.7% for the 18 patients with less than eight nodules (P=.06). Fourteen patients presented with bilateral lung metastases and had a 5-year EFS rate of 35.7% compared with the 12 patients who presented with unilateral involvement and had a 5-year EFS rate of 75.0% (P=.03). The hematopoietic toxicity experienced by the patients during the entire regimen was relatively mild. Seven patients had renal toxicity characterized by hypophosphatemia and/or hypokalemia.CONCLUSION:This ifosfamide-containing regimen is tolerable and effective in the treatment of patients with osteosarcoma (OS) who present with lung metastases. However, better regimens are required for this group of patients.

Purpose: To evaluate risk factors for clinical cardiotoxicity from anthracycline chemotherapy in children with cancer and to estimate the relative risk associated with each factor singly and with different combinations of risk factors. Patients and Methods: The study population consisted of 6493 children with cancer who had received anthracycline chemotherapy on Pediatric Oncology Group protocols during the period from 1974 to 1990. Cardiotoxicity, defined as congestive heart failure not due to other causes, abnormal measurements of cardiac function that prompted the discontinuation of therapy, or sudden death from presumed cardiac causes, was determined by a review of protocol records. Results: Cardiotoxicity was confirmed in 106 patients (1.6%): 58 had congestive heart failure, 43 had changes in measures of cardiac function that prompted the discontinuation of therapy and five died suddenly from presumed cardiac causes. In a multivariate analysis, factors contributing to the relative risk (RR) of toxicity were a cumulative dose of anthracycline≥550 mg/m2 of body-surface area (RR=5.2), a maximal dose of 50 mg/m2 (RR=2.8), female sex (RR=1.9), black race (RR=1.7), the presence of trisomy 21 (RR=3.4) and exposure to amsacrine (RR=2.6). The relative risk of early clinical cardiotoxicity increased with increasing numbers of risk factors and was projected to exceed 405 when all six statistically significant risk factors were present. Conclusion: Early clinical cardiotoxicity in children treated with anthracycline is rare. A high maximal dose, or cumulative dose of anthracycline, female sex, black race, the presence of trisomy 21 and treatment with amsacrine increase the risk for anthracycline-associated cardiotoxicity. The cumulative effect of multiple risk factors can be estimated as the product of the relative risks associated with each.

PURPOSE To determine the incidence of clinical cardiotoxicity from anthracycline chemotherapy in children with cancer and to identify associated risk factors. PATIENTS AND METHODS The study population consisted of 6,493 children with cancer who had received anthracycline chemotherapy on Pediatric Oncology Group (POG) protocols from 1974 to 1990. Cardiotoxicity, defined as congestive heart failure not due to other causes, abnormal measurements of cardiac function that prompted discontinuation of therapy, or sudden death from presumed cardiac causes, was determined by a review of protocol records. RESULTS Cardiotoxicity was confirmed in 106 patients (1.6%): 58 had congestive heart failure, 43 had changes in measures of cardiac function that prompted the discontinuation of therapy, and five died suddenly from presumed cardiac causes. In a multivariate analysis, factors that contributed to the relative risk (RR) of toxicity were a cumulative anthracycline dose > or = 550 mg/m2 of body-surface area (RR = 5.2), maximal dose > or = 50 mg/m2 (RR = 2.8), female sex (RR = 1.9), black race (RR = 1.7), presence of trisomy 21 (RR = 3.4), and exposure to amsacrine (RR = 2.6). Cardiotoxicity within 1 year after the completion of anthracycline treatment (early cardiotoxicity) represented 89.5% of all cases. CONCLUSION Early clinical cardiotoxicity in children treated with anthracycline is rare. A high maximal dose, or cumulative dose of anthracycline, female sex, black race, presence of trisomy 21, and treatment with amsacrine increase the risk for anthracycline-associated cardiotoxicity.

PURPOSE:To assess long-term pulmonary effects of multiagent chemotherapy, we studied serial pulmonary function tests (PFTs) of 35 children with osteosarcoma up to 12 years after diagnosis.PATIENTS AND METHODS:We analyzed 84 sets of PFTs from 35 patients diagnosed with osteosarcoma between 1981 and 1991. They received bleomycin, cyclophosphamide, methotrexate, doxorubicin, cisplatin, and actinomycin D over 9-12 months and we performed PFTs from 3 days to 152 months after diagnosis. Time period I included 36 PFTs (43%) performed between 1 and 5 months from diagnosis, time period II included 20 PFTs (24%) performed between 8 and 12 months from diagnosis, and time period III included 28 PFTs (33%) performed between 12 and 119 months from diagnosis. Total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and carbon monoxide diffusing capacity (DLCO) were analyzed. Maximal respiratory pressures and arterial blood gases were measured to assess muscle weakness and gas exchange, respectively. Mean differences in PFTs were compared among the three time periods and between time period pairs.RESULTS:All mean PFT values showed significant differences among time periods. Significant decline in DLCO; (P=.012), TLC (P=.020), and FEV1 (P=.028) between time periods I and II were noted followed by a trend towards recovery between time periods II and III. Time periods I and III were not significantly different from one another. Mean PFTs performed after 2 years of diagnosis were not different from mean PFTs performed from diagnosis at 2 years.CONCLUSION:This dosage regimen of multi-agent chemotherapy for osteosarcoma patients caused a transient, but significant, decline in PFTs within 8-12 months after administration but appears to cause no significant long-term pulmonary function abnormalities.

PURPOSE:The combination of ifosfamide (I) and etoposide (E) was useful in salvaging patients with recurrent/resistant malignant solid tumors of childhood. Carboplatin (C), active against a number of pediatric cancers, was added to I and E to form a three-drug combination called ICE to improve the response rate. PATIENTS AND METHODS:ICE, consisting of I 1.5 g/m2 plus E 100 mg/m2 i.v.q.d. x 3 plus C i.v. on day 3 only, was given in 21-28-day intervals. C was started at 300 mg/m2, and the dose was escalated in 25% increments, with three evaluable patients treated at each level. RESULTS:Ninety-two patients were enrolled in this phase I/II study between July 1990 and April 1993. A total of 331 courses of ICE was administered. Median courses of ICE received were three (range, 1-16). The maximum tolerated dose (MTD) for C when used in combination was found to be 635 mg/m2. The response rate for ICE at the MTD for C was complete response (CR) 26% and CR + partial response (PR) 53%. The response was even better in those who received C at the MTD: 32% achieving a CR and 63% a CR + PR. Pancytopenia was the dose-limiting toxicity. Thirteen episodes of bacterial infection were reported, none fatal. Only one patient developed a Fanconi-like syndrome. CONCLUSION:The MTD of C when used with I and E was found to be 635 mg/m2. The overall CR + PR rate for all patients treated at all C dose levels was 53%. Best responses were seen in non-Hodgkin's lymphoma, neuroblastoma, soft tissue sarcomas, and Wilms' tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

PURPOSE:To determine the frequency of osteopathy in patients treated with high-dose, short-term, intravenous methotrexate for osteosarcoma and whether this complication varies with patient age and methotrexate dose.MATERIALS AND METHODS:Radiographs and available scintigrams of 87 patients with osteosarcoma who received high-dose methotrexate were reviewed retrospectively for severe osteopenia, dense zones of provisional calcification, insufficiency fractures, and involvement of multiple bones. At least three of these radiographic abnormalities were required for the diagnosis of osteopathy. Patients with bone metastases were excluded.RESULTS:Eight patients (cumulative dose, 60-144 g/m2) exhibited adverse skeletal findings similar to those described in children with leukemia who received low-dose maintenance methotrexate. Images showed severe osteopenia (n = 8), dense zones of provisional calcification (n = 8), multiple bone involvement (n = 6), and insufficiency fractures (n = 6). Most commonly affected sites were the distal tibia (n = 7), distal radius and proximal humerus (n = 3), and calcaneus and public ramus (n = 2). The affected patients were significantly younger (mean age, 9.2 years; P < .001) than the 79 unaffected patients (mean age, 14.9 years).CONCLUSION:Osteopathy occurs in approximately 9% of children who receive high-dose methotrexate for osteosarcoma and is substantially more likely to occur in younger patients. The complication rate was not directly dose dependent.

This study was designed to test if the activity of a phase II agent, ifosfamide, would have been underestimated if it was tested exclusively in a population of children and young adults with recurrent osteosarcoma. The response rate to ifosfamide was compared in patients younger than 30 years of age with previously untreated osteosarcoma with metastases at diagnosis and/or unresectable primary tumors (stratum 1) with that of patients with recurrent osteosarcoma following adjuvant chemotherapy who were not previously exposed to ifosfamide (stratum 2). Evaluation of response was conducted 3 weeks after two courses of ifosfamide (2400 mg/m2 x 5 days) were administered 3 weeks apart. Nine of 33 (27%) evaluable patients in stratum 1 responded (1 complete and 8 partial responses) to ifosfamide. Among 30 evaluable patients in stratum 2, only 3 (10%) responded (1 complete and 2 partial responses; P = .04) Both groups of patients received equal doses of ifosfamide and experienced comparable toxicities. Results from this study suggest that the activity of new agents will be underestimated if tested in a population of heavily pretreated patients with recurrent disease. When possible, new chemotherapeutic agents should be tested in patients with a poor prognosis who have not been exposed to chemotherapy.

BACKGROUNDLate cardiotoxic effects of doxorubicin are increasingly a problem for patients who survive childhood cancer. Cardiotoxicity is often progressive, and some patients have disabling symptoms. Our objective was to identify risk factors for late cardiotoxicity.METHODSWe examined echocardiograms from 120 children and adults who had received cumulative doses of 244 to 550 mg of doxorubicin per square meter of body-surface area for the treatment of acute lymphoblastic leukemia or osteogenic sarcoma in childhood, a mean of 8.1 years earlier. Measurements of blood pressure and left ventricular function, contractility (measured as the stress-velocity index), end-diastolic posterior-wall thickness, end-diastolic dimension, mass, and afterload (measured as end-systolic wall stress) were compared with sex-specific values from a cohort of 296 normal subjects.RESULTSAll echocardiographic measurements were abnormal at follow-up a minimum of two years after the end of therapy, with more frequent and severe abnormalities in female patients. In a multivariate analysis, female sex and a higher cumulative dose of doxorubicin were associated with depressed contractility (P < or = 0.001), and there was an interaction between these two variables. Independent and significant associations were found between a higher rate of administration of doxorubicin and increased afterload (P < or = 0.001), left ventricular dilatation, and depressed left ventricular function; between a higher cumulative dose and depressed left ventricular function (P < or = 0.001); between a younger age at diagnosis and reduced left-ventricular-wall thickness and mass and increased afterload; and between a longer time since the completion of doxorubicin therapy and reduced left-ventricular-wall thickness and increased afterload (P < or = 0.001).CONCLUSIONSFemale sex and a higher rate of administration of doxorubicin were independent risk factors for cardiac abnormalities after treatment with doxorubicin for childhood cancer; the prevalence and severity of abnormalities increased with longer follow-up.

Second malignancies following treatment for osteosarcoma are unusual. Breast cancer occurring in patients with osteosarcoma has been reported following therapeutic chest irradiation. We now report three cases of breast cancer occurring in young women who were successfully treated for osteosarcoma. These women had not received therapeutic chest irradiation and in two of the three women there was no family history of breast cancer. Peripheral blood was available for study from one case. Of import, this case demonstrated a germline mutation in exon 7 of the tumor suppressor gene, p53. The mutation was detected by constant denaturing gradient gel electrophoresis and confirmed by DNA sequencing. In this particular patient, inactivation of the p53 gene may be involved in the development of both the first and second malignancy.

I was fascinated by your decision to publish the recent article "Monitoring for Anthracycline Cardiotoxicity" by Dr Lipshultz et al. (Pediatrics. 1994;93:433-437). The article appears to be nothing more than a somewhat delayed letter to the Editor in response to the previously published "Guidelines for Cardiac Monitoring of Children During and After Anthracycline Therapy: Report of the Cardiology Committee of the Children's Cancer Study Group" (CCSG) (Pediatrics. 1992;89:942-949). In attempting to refute the recommendations of a national panel of experts, the authors present their opinions supported by no new data.

OBJECTIVE:To review the basis for recommendations of the Cardiology Committee of the Children's Cancer Study Group, published in Pediatrics, for serial cardiac monitoring of cancer patients during anthracycline therapy and reduction of therapy should cardiac studies show abnormalities.DESIGN:Because the effects of overall morbidity and mortality should be considered when a recommendation is made to withhold potentially lifesaving chemotherapy based on abnormal cardiac findings of patients without clinical evidence of cardiac dysfunction, supporting studies referenced in the published recommendations were reviewed. Specifically, studies were evaluated to determine whether a reduction in anthracycline dose, as a result of abnormal cardiac findings by monitoring, reduced cardiac morbidity and related mortality compared with a prospectively followed control population without dose modification. In addition, the effects of cardiac monitoring and subsequent anthracycline dose modification on oncologic morbidity and mortality were reviewed in these studies. Finally, the contributions of the cardiac and oncologic effects of dose modification were examined to determine the effect of this change in therapy on overall morbidity and mortality.RESULTS:None of the studies cited in developing these recommendations prospectively determined, with controls, the effects of cardiac monitoring and anthracycline dose modification on cardiac, oncologic, or overall morbidity and mortality. Therefore, none of the studies cited in support of cardiac monitoring and subsequent dose reduction demonstrated the efficacy of such an approach. In the absence of such data, concerns are raised as to whether such a monitoring program with subsequent dose modification might do more harm than good. In addition, none of the methods of screening for anthracycline cardiotoxicity has been shown to be adequately predictive of early or late cardiac outcomes. Finally, adoption of these recommendations would inhibit the investigation of the efficacy of the proposed plan.CONCLUSION:Given the absence of supportive data and the potential to do harm, no recommendation for dose modification based on abnormal cardiac findings in patients without clinical evidence of cardiotoxicity can be endorsed, including those of the Cardiology Committee of the Children's Cancer Study Group. When clinical evidence of cardiotoxicity is present, anthracycline dose modification is recommended. A prospective controlled study to determine the effects of dose modification based on cardiac test results is indicated.