Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study.

Between 1986 and 1990, the Pediatric Oncology Group conducted a study in which 198 children younger than 3 years of age with malignant brain tumors were treated with prolonged postoperative chemotherapy in an effort to delay irradiation and reduce long-term neurotoxicity. Children younger than 2 years of age received 24 months of chemotherapy followed by irradiation, and those between 2 and 3 years of age received 12 months of chemotherapy plus irradiation. Chemotherapy was given in 28-day cycles (AAB, AAB), with cycle A = vincristine (0.065 mg/kg) intravenously on days 1 and 8 and cyclophosphamide (65 mg/kg) intravenously on day 1, and cycle B = cisplatinum (4 mg/kg) intravenously on day 1 and etoposide (6.5 mg/kg) intravenously on days 3 and 4. Five of the 198 children developed second malignancies, with a cumulative risk at 8 years of 11.3% (95% confidence interval [CI], 0-39%). Four of the five second malignancies occurred in children younger than 2 years of age at diagnosis, with a cumulative risk at 8 years of 18.9% (CI, 0-70%). Initial diagnoses were choroid plexus carcinoma (2 children), ependymoma (1 child), desmoplastic infantile ganglioglioma (2 children), and medulloblastoma (1 child). Duration from diagnosis of initial tumor to second malignancy was 33, 35, 57, 66, and 92 months. Three children younger than 2 years of age developed lymphoproliferative disease, that is, myelodysplastic syndrome (2 children), both with monosomy 7 deletions, and acute myelogenous leukemia (1 child), after 24 to 26 cycles of chemotherapy, including 8 cycles of etoposide. Two of 3 received craniospinal irradiation (2,560/3,840 cGy) and (3,520/5,320 cGy). Time to second malignancy was 7 years 8 months, 4 years 9 months, and 2 years 9 months. Two children developed solid tumors, at 5 years 6 months and 2 years 11 months, respectively, after initiation of treatment. A sarcoma developed after 26 cycles of chemotherapy and no irradiation, and a meningioma developed after 12 cycles of chemotherapy and local craniospinal irradiation. Potential causative factors for this high rate of secondary malignancies include prolonged use of alkylating agents and etoposide with or without irradiation.

Prognostic factors in infants and very young children with intracranial ependymomas.

The Pediatric Oncology Group (1986-1990) conducted a study in which 48 children <3 years of age with intracranial ependymomas were treated with prolonged postoperative chemotherapy (CT) and delayed RT. Thirty-one children, 0-23 months of age at diagnosis (Gp A) received 2 years of CT followed by RT; while 17 children, 24-36 months of age at diagnosis (Gp B) received CT for 1 year followed by radiation. One-year survivals were 87% (Gp A) and 94% (Gp B) and 2-year survivals were 67% (Gp A) and 82% (Gp B). In subsequent years a significant divergence in survivals according to age has been noted (p = 0.04). Five-year survivals were 25.7% (Gp A) vs. 63.3% (Gp B). The curves began to diverge 1 year following diagnosis. Other than age, the only significant prognostic factor was degree of surgical resection: 5-year survivals were 66% (total resection) vs. 25% (subtotal resection). Neither the presence of metastases, degree of anaplasia nor the degree of surgical resection varied significantly according to age at diagnosis. The most likely reason for the difference in survivals between the two age groups relates to the timing of radiation following CT, i.e., 1-year delay in children 24-36 months of age compared to a 2-year delay in children 0-23 months of age. An alternative but less likely hypothesis is that ependymomas in the younger children have a more aggressive biology. In contrast, survivals in the 24- to 36-month group are much better than previous reports in the literature suggesting that prolonged postoperative CT may allow both a delay in CRT as well as provide improved survivals. Based on these results, future treatment trials should emphasize maximal surgical resection and a delay in radiation of no more than 1 year.

Late effects of therapy in survivors of Ewing's sarcoma family tumors.

PURPOSE: This late effects study was designed to determine if survivors of Ewing's sarcoma family tumors (ESFT) had adverse outcomes in employment, marital status, fertility, and functional status when compared to sibling controls. SUBJECTS AND METHODS: Eighty-nine survivors (case subjects) of ESFT treated at the National Cancer Institute between 1965 and 1992 and 97 sibling controls completed a questionnaire probing aspects of quality of life. The answers from case subjects were compared to pooled and matched sibling controls for all key variables. Odds ratios (OR) and p values from pooled analyses are presented. RESULTS: Although case subjects and controls did not differ in educational achievement, case subjects were less likely to be employed full-time (OR 0.4, p < 0.01), to be married (OR 0.2, p < 0.01), and to have children (OR 0.3, p < 0.01). Their most common treatment-related difficulties included permanent hair and skin changes (43%), lung problems (18%), neurologic problems (14%), visual difficulties (10%), second malignancy (7%), and amputation (5%). Functional status, measured by Karnofsky performance scale, was also adversely affected in case subjects. Case subjects did not differ from sibling controls in health care insurance status or in utilization of health services. CONCLUSIONS: Important aspects of life such as employment, marital status, fertility, and functional status are affected in survivors of ESFT. More studies are needed to better define the health status of adult survivors of pediatric cancer and the impact of cancer in adolescence on psychosocial development.

Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas.

BACKGROUND: An excess risk of second malignancies has been reported in survivors of Ewing's sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewing's sarcoma and to identify possible causal factors. METHODS: Information was derived from a data base that included 266 survivors of Ewing's sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated. RESULTS: After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P = .002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy. CONCLUSION: The overall risk of second malignancies after Ewing's sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.

Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing's sarcoma family of tumors.

BACKGROUND: This study was conducted to determine the feasibility of, and improve outcome by, incorporating ifosfamide and etoposide (IE) into the therapy of newly diagnosed patients with Ewing's sarcoma family of tumors of bone and soft tissue. METHODS: Fifty-four newly diagnosed patients received 7 cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC) and 11 cycles of IE. Radiation therapy after the fifth chemotherapy cycle was the primary approach to local control. RESULTS: Actuarial 5-year event-free survival (EFS) and overall survival rates were 42% and 45%, respectively, with a median duration of potential follow-up of 6.8 years. EFS was significantly better for patients with localized tumors than for those with metastatic lesions (64% v. 13%, P < 0.0001). Actuarial local progression-free survival at 5 years was 74%, and did not correlate with primary tumor size or site, histologic subtype, or the presence of metastases. Febrile neutropenia developed after 49% of cycles, and clinical or sub-clinical cardiac dysfunction was common (7% and 40% respectively). There were four toxic deaths and one case of secondary myelodysplastic syndrome. CONCLUSIONS: Despite substantial toxicity, the integration of IE into the front-line, VAdriaC-based therapy of patients with Ewing's sarcoma family of tumors is feasible and appeared to significantly improve the outcome for patients with high risk localized tumors, but had no impact on the poor prognosis of patients with metastatic tumors. Local control can be achieved in the vast majority of patients using radiotherapy exclusively, even among patients with bulky, central axis tumors. Longer follow-up is needed to evaluate the late effects of this intensive therapy.

Phase II evaluation of topotecan for pediatric central nervous system tumors.

BACKGROUND: Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS: Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS: There were no complete or partial responses in the patients with high grade glioma (n=9), medulloblastoma (n=9), or brain stem glioma (n=14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose escalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS: Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors.

Treatment of infants with malignant gliomas: the Pediatric Oncology Group experience.

Although survivals of infants with malignant brain tumors are worse than any other age group, one possible exception to this rule are the malignant gliomas. Eighteen children less than 3 years of age with malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma and malignant glioma) were treated on the Pediatric Oncology Group regimen of prolonged postoperative chemotherapy and delayed irradiation, (1986-1990). Of 10 children evaluable for neuroradiologic response, 6 had partial responses (> 50% reduction) to two cycles of cyclophosphamide and vincristine. Progression free survivals at 1,3 and 5 years were 54.25% +/- 12, 43% +/- 16 and 43% +/- 23 respectively. Survivals at 5 years were 50% +/- 14. Four children were not irradiated after 24 months of chemotherapy due to parental refusal and none have developed recurrent disease. Neither degree of surgical resection, presence or absence of metastases, nor pathology influenced survival but this may reflect small sample size. This study suggests that some malignant gliomas in infants are chemotherapy sensitive and may be associated with a good prognosis. Why infants with these high-grade gliomas fare better than adults is not clear. It is likely that there is something intrinsically different about them that cannot be identified on routine pathologic examination.

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

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.

PURPOSE: We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients. METHODS: Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities. RESULTS: Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity. CONCLUSION: ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.

Malignant melanoma of soft parts involving the head and neck region: review of literature and case report.

Malignant melanoma of soft parts (MMSP) was originally described as a distinct entity by Enzinger in 1965 and was termed "clear cell sarcoma of tendons and aponeuroses" because of its association with tenosynovial structures. It has been shown immunophenotypically and ultrastructurally that this tumor is derived from neuroectoderm and shares a number of features with cutaneous melanoma. Over 95% of MMSPs present in the extremities, with the head and neck region (1.9%) being an unusual site. This study presents an additional case of MMSP of the head and neck region involving the posterior cervical region in a 15-year-old Hispanic male and reviews the literature on MMSP. Ultrastructural examination showed rudimentary cell attachments, smooth cell membranes, discontinuous basal lamina, scanty glycogen, and occasional premelanosomes in some tumor cells. Cytogenetic analysis showed a reciprocal translocation between the long arms of chromosomes 12 and 22 [t(12:22)(q13;q12.2)], characteristic for MMSP and not seen in cutaneous melanoma. Survival in MMSP has been correlated with tumor size, tumor necrosis, and ploidy status. Overall reported clinical outcome for this tumor is as follows: died of disease, 45%; alive with disease, 23%; no evidence of disease, 30%; and died of other causes, 2%. MMSP represents a distinct entity with a characteristic ultrastructural appearance and a tumor defining cytogenetic translocation.

Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma. Pediatric Oncology Group.

Eleven infants with pineoblastomas were treated with prolonged postoperative chemotherapy in an attempt to delay radiation and reduce neurotoxicity. These infants were part of the Pediatric Oncology Group infant brain tumor study but the outcome of infants with pineoblastomas was not previously reported. Ages ranged from 1 month to 35 months, with eight of 11 < or = 12 months at diagnosis. Four had + cytology and three had + myelograms at diagnosis. The majority had partial surgical resection (25-75% reduction in tumor) and 10 had shunts. Chemotherapy consisted of two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. Craniospinal radiation was planned following completion of either 2 years of chemotherapy (children less than 24 months at diagnosis) or following one year (children 24-36 months at diagnosis). Neuroimaging results following two cycles of cyclophosphamide and vincristine were one partial response, five stable disease, and five progressive disease. There were no responders in the leptomeninges. All children ultimately failed chemotherapy (2 months-11 months). Nine failed in the primary site. Of those eight children in whom a metastatic workup was performed at time of progression, all had evidence of leptomeningeal disease. Six received radiation following failure on chemotherapy. All failed either in the primary site, leptomeninges or extraneurally (peritoneal cavity). All children died. Survival following diagnosis ranged from 4 months to 13 months. This chemotherapy regimen was neither effective in controlling tumor in the primary site nor in treating or preventing leptomeningeal spread.

A phase II evaluation of thiotepa followed by other multiagent chemotherapy regimens in infants and young children with malignant brain tumors.

BACKGROUND: Chemotherapy may be used to delay the need for cranial irradiation in infants and young children with malignant central nervous system (CNS) tumors. The polyfunctional alkylator thiotepa (TT) possesses significant in vitro and in vivo activity in many central nervous system tumors. Before the introduction of a multiagent chemotherapy previously shown to be active in such tumors, thiotepa alone was evaluated in an upfront therapeutic window. METHODS: Twenty young children with CNS tumors (19 newly diagnosed, 1 recurrent) were treated with two cycles of TT before response evaluation. Patients on thiotepa without disease progression went on to receive further chemotherapy consisting of alternating cycles of cyclophosphamide plus vincristine, cisplatin plus etoposide, and further TT. Patients with disease progression received radiation therapy. RESULTS: Low objective rates of response and poor survival led to early study termination. Of 17 patients evaluable for response, 6 (35%) demonstrated disease progression during initial TT therapy. Only two objective responses were noted, both in patients with medulloblastoma. Among the 19 patients evaluable for survival, the overall and progression free survivals were 45% and 20%, respectively, at 3 years postdiagnosis. Myelosuppression was the dominant treatment-related toxicity. CONCLUSIONS: Although the numbers of patients were small, thiotepa as used in this study was associated with a poor objective response rate and an unacceptably high rate of disease progression. These results may be partly related to TT's significant myelosuppressive effects and the postponement of more effective chemotherapy.

Atypical cytogenic aberrations in two childhood peripheral primitive neuroectodermal tumors.

Atypical cytogenetic abnormalities were detected in peripheral primitive neuroectodermal tumors (PPNET) of the extremity in two children. One had an osseous tumor with a balanced reciprocal translocation, t(5;9)(q22;q32), and had a complete response to therapy. The other had a non-osseous tumor with an interstitial deletion, del(18)(q12.2q21.2), was resistant to combination therapy, and at autopsy had evidence of possible clonal evolution with the karyotype 46,XX der(8)t(8;8)(p11.2;q13), inv(16)(p13.2q12),del(18)(q12.2q21.2). Neither tumor demonstrated the t(11;22)(q24;q12) typically found in Ewing's sarcoma and PPNET, suggesting heterogeneity of the cytogenetic aberrations seen in this rare childhood malignancy.

Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy.

BACKGROUND: Inadequate reconstitution of CD4+ T lymphocytes is an important clinical problem complicating chemotherapy, human immunodeficiency virus infection, and bone marrow transplantation, but relatively little is known about how CD4+ T lymphocytes regenerate. There are two main possibilities: bone marrow-derived progenitors could reconstitute the lymphocyte population using a thymus-dependent pathway, or thymus-independent pathways could predominate. Previous studies have suggested that the CD45RA glycoprotein on CD4+ T lymphocytes is a marker for progeny generated by a thymus-dependent pathway. METHODS: We studied 15 patients 1 to 24 years of age who had undergone intensive chemotherapy for cancer. The absolute numbers of CD4+ T lymphocytes in peripheral blood and the expression of CD45 isoforms (CD45RA and CD45RO) on these lymphocytes were studied serially during lymphocyte regeneration after the completion of therapy. Radiographic imaging of the thymus was performed concomitantly. RESULTS: There was an inverse relation between the patients' ages and the CD4+ T-lymphocyte counts six months after therapy was completed (r = -0.92). The CD4+ recovery correlated quantitatively with the appearance of CD45RA+CD4+ T lymphocytes in the blood (r = 0.64). There was a higher proportion of CD45RA+CD4+ T lymphocytes in patients with thymic enlargement after chemotherapy than in patients without such enlargement (two-sided P = 0.015). CONCLUSIONS: Thymus-dependent regeneration of CD4+ T lymphocytes occurs primarily in children, whereas even young adults have deficiencies in this pathway. Our results suggest that rapid T-cell regeneration requires residual thymic function in patients receiving high-dose chemotherapy.

Is neuro-ectodermal differentiation of Ewing's sarcoma of bone associated with an unfavourable prognosis?

Among Ewing's sarcoma (ES) of bone and related entities are tumours with neuro-ectodermal features that could represent a biologically distinct type. In order to assess the prognostic significance of the various forms of ES, a retrospective joint study involving three cancer centres in Europe and the U.S.A. was initiated. The material from 315 primary ES was reviewed by a panel of five pathologists and classified as typical ES (220 cases), atypical ES (48 cases) or ES with neuro-ectodermal features (47 cases). Prognostic factor analysis on treatment failure-free survival was performed using the Cox model. It included histopathological classification, initial patient characteristics, clinical presentation and treatment type. After multivariate analysis, in addition to treatment type (P < 0.001), metastases (P = 0.003) and proximal tumour location (P = 0.006), two histopathological parameters correlated with poor treatment failure-free survival, the presence of filigree pattern (P = 0.044) and dark cells (P = 0.043). We conclude that ES with neuro-ectodermal features does not appear to have a different outcome to the other subtypes.

Postoperative chemotherapy and delayed radiation in infants and very young children with choroid plexus carcinomas. The Pediatric Oncology Group.

Eight infants with choroid plexus carcinomas were treated with surgery, prolonged postoperative chemotherapy and delayed radiation. The results suggest that some infants with choroid plexus carcinomas can be successfully treated with multimodality therapy, even allowing children with less than a gross total resection to have prolonged disease-free intervals.

Lymphocyte depletion during treatment with intensive chemotherapy for cancer.

Recently we have observed an increased incidence of opportunistic infections in patients treated with intensive chemotherapy for cancer. Because T-cell depletion is associated with similar clinical events in human immunodeficiency virus infection and after bone marrow transplantation, we have analyzed peripheral blood lymphocyte populations in a series of patients during treatment with intensive chemotherapy for cancer. Although neutrophil, monocyte, and platelet numbers consistently recovered to greater than 50% of pretreatment values after each sequential cycle of therapy, lymphocyte numbers did not recover within the same time period. B cells decreased rapidly from a mean value of 149 +/- 46/mm3 before chemotherapy to 4 +/- 1/mm3 during chemotherapy (P = .01). CD4+ T cells decreased from a mean of 588 +/- 76/mm3 before chemotherapy to 105 +/- 28/mm3 during chemotherapy (P = .0002) and CD8+ T cells decreased from a mean of 382 +/- 41/mm3 before chemotherapy to 150 +/- 46/mm3 during chemotherapy (P = .0009). Natural killer cell numbers did not show significant declines (171 +/- 30/mm3 before, 114 +/- 24/mm3 during, P = .19). Based on the history of opportunistic complications in patients with other disorders who display similar degrees of CD4+ T-cell lymphopenia and preliminary observations in this population, immune incompetence could surface as a dose-limiting toxicity for highly dose-intensive chemotherapy regimens.