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Keywords:

  • childhood cancer therapy;
  • late effects;
  • long-term follow-up

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISCUSSION
  5. REFERENCES
  6. Supporting Information

Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects. Pediatr Blood Cancer 2013; 60: 1083–1094. © 2013 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISCUSSION
  5. REFERENCES
  6. Supporting Information

The prognosis of children and adolescents with solid tumors, most of which are malignant, has improved dramatically over the past five decades. For the most common of these tumors, 5-year survival now exceeds 70%.1 Although select patient groups require less morbid surgical procedures and abbreviated courses of chemotherapy, the majority need intensive systemic and multimodal local interventions that may cause unavoidable long-term toxicity.

Monitoring of the long-term health of survivors of pediatric solid tumors identifies cancer-related morbidities for which early detection, prevention, and remediation are needed. In a companion article 2 in Pediatric Blood and Cancer, we recently described the evolution of major therapeutic trends for pediatric hematological malignancies. The current review provides a complementary overview of solid tumors that: (1) summarizes major trends in the evolution of pediatric solid tumor therapy since 1960; (2) identifies treatment-specific exposures in cohorts treated before 2000 that may affect patients treated on clinical trials during the past decade; and (3) identifies the extent to which studies of cohorts of long-term survivors can predict the risk of late effects in patients receiving contemporary treatment.

Central Nervous System Tumors

Tumors of the central nervous system (CNS) are the most frequent group of non-hematopoietic tumors of children and adolescents. Therapeutic approaches for these tumors, and the evolution of these approaches has differed according to tumor type, location and biology. Advances in neuroimaging, neuropathology, and neurobiology have better defined CNS tumors, and progress in neurosurgery, radiation therapy (RT) techniques, and incorporation of chemotherapy has improved disease control and functional outcomes.

Low-grade gliomas (LGG) are the most common pediatric CNS tumors, and pilocytic astrocytoma is the dominant histology. Complete surgical resection is usually curative of cerebellar, cerebral, and thalamic lesions (Supplementary Table I). A prospective, multi-institutional, non-randomized study of LGG found 8-year survival to be 96%; progression-free survival (PFS) was 93% after gross total resection (GTR) but only 55% after incomplete resection. Overall survival was affected by site, as patients with optic chiasmatic/hypothalamic tumors fared less well 3.

Optic chiasmatic/hypothalamic LGG are responsive to chemotherapy and RT but are problematic due to their central location associated ophthalmic and endocrine impairment, younger age of onset, and association with neurofibromatosis type 1. By the 1970s, long-term disease control, often with preservation of vision, was achieved by RT 4; subsequently, 10-year PFS rates approximated 75% in a non-randomized, single institution study after the introduction of three-dimensional RT techniques 5. RT-related toxicities (especially neurovascular compromise and neurocognitive deficits in younger children) prompted the evaluation of primary chemotherapy in the 1990s 6, 7. Five-year PFS as high as 75% was achieved by treatment with vincristine (VCR) and carboplatin (CBDCA) (±temozolomide), which are now the standard initial therapy for progressive or symptomatic centrally located LGG in younger children (Supplementary Table I) 8. Durable disease control may ultimately require post-progression RT 5, 9.

The most common malignant CNS tumor is medulloblastoma. Post-operative wide-field RT and staging (i.e., extent of resection and subarachnoid metastasis) cured more than 25% of children before 1970 10. Improved surgery and craniospinal irradiation (CSI) (35 Gy) with a boost to the posterior fossa (54 Gy) resulted in 5-year PFS rates of 60–70% for the more than 75% of children with average-risk disease (localized/M0 with complete or near complete resection) 11, 12. Reduction of CSI to 23.4 Gy in 13 fractions was demonstrated in a multi-institutional, randomized trial in the 1990s to be safe when cisplatin (CDDP)-based chemotherapy was added. Five-year EFS was 81 ± 2.1% among average-risk cases, and did not differ significantly between those who received CDDP, VCR and CCNU and those who received CDDP, VCR and cyclophosphamide (CTX) (Table I) 13, 14. Modifications of RT technique and reduction of the volume of the boost to the tumor bed appeared to diminish the risk of neurocognitive deficits and ototoxicity in patients receiving 3D conformal or intensity-modulated RT (3D-CRT, IMRT) and amifostine with CDDP further reduced ototoxicity 15. For high-risk disease, dose-intensive chemotherapy (CDDP, CTX, VCR) with CSI to 36–39.6 Gy, or concurrent CBDCA with RT, achieved disease control rates of 65–70% 16, 17.

Table I. Evolution of Therapy for Medulloblastoma
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
19601970 and 19801990Post-2000 
ChemotherapyNoneCombinationCombinationRisk-adaptedRisk-adapted
  1. CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; HCT, hematopoietic cell transplant.

Agents CCNUCCNUCyclophosphamideCyclophosphamide
VincristineVincristineVincristineVincristine
 CisplatinCisplatinCisplatin
  ± HCT 
  Addition of etoposide for high-risk 
Dose-intensity/duration 8 Cycles Myeloablative chemotherapy with autologous HCT after radiation therapy 
RadiationCraniospinal radiation therapyCraniospinal radiation therapyCraniospinal radiation therapyTumor bed
Brain and spinal cord (35–40 Gy)Brain and spinal cord (24–40 Gy)Tumor bed or posterior fossa (54–56 Gy) conformalPosterior fossa
Posterior fossa (50–55 Gy)Posterior fossa (54–56 Gy)Brain and spinal cord (24–40 Gy)Brain and spinal cord
SurgeryTotal or subtotal resection 

Management of CNS tumors in young children is particularly challenging. Clinical studies of primary chemotherapy for embryonal tumors (medulloblastoma, supratentorial primitive neuroectodermal tumors [PNET], and atypical teratoid/rhabdoid tumors [AT/RT]) in young children began in the 1980s 18–20. Drug regimens included CDDP, etoposide (VP16), CTX, and VCR; the German HIT trials added high-dose systemic and intrathecal methotrexate. RT evolved from systematic delayed, response-adjusted CSI to planned local, 3D-CRT or IMRT, or proton beam regimens for M0 tumors or elective, attenuated CSI for consolidation or salvage 18, 21. A recent multi-institutional, non-randomized treatment study reported 5-year PFS of 58 ± 9% in medulloblastoma and 82 ± 9% in resected M0 tumors 20.

Ependymomas present most commonly in the IVth ventricular region. Complete resection is curative for differentiated supratentorial ependymomas.22. Long-term local disease control has been reported for 87.3% (95% confidence interval 77.5–97.1%) of patients who participated in a single institution, non-randomized study of high-dose 3D-CRT after maximal tumor resection. Local therapy shifted to RT even in younger children after studies indicated preservation of neurocognitive function (Supplementary Table II) 23, 24. Radical resection, achievable in almost all cases, is sometimes associated with significant post-operative bulbar deficits. Adjuvant chemotherapy has yet to show a benefit in patients with resected ependymomas.

In summary, post-resection radiation remains a crucial component of therapy for most CNS tumor subtypes, although contemporary approaches optimize protection of normal tissues. Chemotherapy, introduced in the 1970s, has permitted the delay of CNS irradiation in young children and improved disease control when incorporated into combined-modality regimens for specific subtypes.

Retinoblastoma

Retinoblastoma (RB), the most frequent primary ocular tumor in children, may occur as non-heritable (usually unilateral) or heritable (usually bilateral) form 25. Unilateral sporadic disease is curable by enucleation, and metastatic disease can usually be prevented by adjuvant chemotherapy. The heritable form, associated with a significant risk of second malignant neoplasm 26, is identifiable by multifocal intra-ocular tumors or a positive family history. For these children, RT is recommended only when surgery, chemotherapy, and focal measures cannot preserve vision in at least one eye. However, 10–15% of children with heritable RB have a single eye tumor and no family history of cancer 27 and are thus indistinguishable from patients with non-heritable, unilateral RB.

Until the 1990s 28 ophthalmologists were the primary caregivers for RB, as surgery was the main treatment 29 and could cure 95% or more of unilateral tumors 30, 31. Bilateral diseases could be cured by enucleation and RT. The challenge of treating RB is to maximize long-term survival while preserving vision. Treatment with external-beam radiation therapy (EBRT) can usually preserve vision in at least one eye but causes severe orbital hypoplasia 32. In the early 1990s, CBDCA and VP16 proved effective in reducing the volume of intra-ocular disease in bilateral RB 33–35. With subsequent focal therapy (cryotherapy, thermotherapy, laser, or scleral radioactive plaque), this approach allowed the preservation of many eyes that would otherwise have required removal or EBRT (Supplementary Table III) 36.

Chemotherapy is used as an adjunct to surgery when there is high risk of metastasis, as in cases of optic nerve, massive choroidal, or scleral invasion 37. The drugs most useful for chemoreduction include CBDCA, VCR, and VP16 38. The addition of subconjunctival CBDCA to intravenous chemotherapy improves the rate of eye and vision salvage 39. Newer RT modalities, such as IMRT and proton beam therapy, may enhance protection of normal tissues 40, 41. Some children with metastatic RB, involving the bone marrow and bones, may be cured by aggressive chemotherapy with the same drugs used for primary therapy and autologous hematopoietic cell transplantation (HCT) 42–44. As treatment of RB changed very little until the end of the 20th century, evaluation of the outcomes of historic therapies remains relevant.

Neuroblastoma

Neuroblastoma, the second most common solid tumor of childhood, behaves variably depending on the clinical and molecular features of tumor and host. In the 1960s, treatment for localized neuroblastoma included surgery with or without RT (Table II). Most patients presented with inoperable or metastatic disease, which was uniformly fatal. Early chemotherapy included large doses of vitamin B12 or actinomycin D (AMD). CTX and VCR were also evaluated, but neither improved survival 45. Other agents available during the 1970s, including doxorubicin (DOX), DTIC, and peptichemio 46, improved the outcome of metastatic disease only in infants <1 year of age. Other drugs, including the epipodophyllotoxins and CDDP, were shown during this period to produce tumor responses in patients with neuroblastoma 47, 48.

Table II. Evolution of Therapy for Neuroblastoma
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
1960197019801990Post-2000
Chemotherapy CombinationCombinationRisk-adaptedRisk-adapted 
AgentsCyclophosphamideVincristineCisplatinNo chemotherapy for stage 1, 2, 4s if asymptomaticCisplatin
VincristineCyclophosphamideVM26/VP16Limited chemotherapy for intermediate riskEtoposide
DTICDoxorubicinIntensive chemotherapy for high riskCyclophosphamide
DoxorubicinCyclophosphamide  Doxorubicin
Peptichemio    
Dose-intensity/durationStandard treatment with 2 cycles beyond remission12 cycles Intensified inductionTesting of tandem autologous HCT, mIBG + ASCTAutologous HCT
    Myeloablative therapy with autologous HCT improves EFS  
Minimal residual disease therapy Preclinical studies of cis-retinoic acid (cisRA)Development of anti-GD2 antibodiescisRA improves EFSCh14.18 + cytokines + cisRA significantly improves EFScisRA
    Phase I/II studies of immunotherapy Ch 14.18
      IL-2
      GM-CSF
RadiationFor localized and regional disease (20–40 Gy)Radiation for spinal cord compression and for liver enlargement 4sLocal radiation to high risk primary site even for resected disease Local radiation to high risk primary site even for resected disease
    No RT to low risk disease No RT to low risk disease
SurgeryOnly for easily resectable localized diseaseUse of neoadjuvant therapy before surgeryComplete resection more important for high risk diseaseINSS staging system dependent on resectionClinical staging with computed tomography and positron emission tomography. 

During the 1980s, cooperative group studies showed that neither chemotherapy nor RT was necessary for treatment of localized neuroblastoma 49, 50. The relative radiosensitivity of neuroblastoma led to reduction of RT doses for those with regional disease 51. In the late 1980s, targeted RT with 131I-mIBG was used extensively in Europe and the US for relapsed neuroblastoma, with significant response rates 52. Induction regimens that incorporated CDDP and epipodophyllotoxins produced response rates as high as 70% 53. Ifosfamide (IFOS) and CBDCA were identified as agents with activity against neuroblastoma 54. Myeloablative therapy followed by autologous or allogeneic HCT produced tumor responses in patients with recurrent neuroblastoma 55. Immunotherapy for neuroblastoma was developed during this decade, with the production of murine monoclonal antibodies that targeted the GD2 ganglioside expressed on more than 95% of neuroblastoma cells 56.

The theme of the 1990s was increased dose intensity. In a randomized trial, patients with high-risk neuroblastoma showed significantly improved EFS with myeloablative chemotherapy and autologous HCT 57. However, the relapse rate was high, and the focus shifted to elimination of minimal residual disease (MRD). Patients treated with 6 months of the differentiating agent isotretinoin after either myeloablative therapy or chemotherapy had significantly better outcomes than those randomly assigned to no further treatment. The best survival was seen among children who received both HCT and isotretinoin 57. New pilot studies have the chimeric Ch14.18, anti-GD2, and GM-CSF, and then with GM-CSF and interleukin-2 (IL-2), demonstrated that the antibody could be combined safely with these additional agents 58.

Contemporary treatment of low- and intermediate-risk NB is similar to that used during previous decades, with continued reduction of intensity according to biologic risk factors. Targeted therapy with 131I-mIBG for high-risk disease has been incorporated into large cooperative trials 59. The significant improvement in EFS, estimated from the date of autologous HCT (post-autologous HCT EFS), provided by myeloablative therapy followed by ch14.18, cytokines, and isotretinoin for MRD, as compared to isotretinoin alone (2-year post-autologous HCT EFS, 66% vs. 46%, P = 0.01), will be the benchmark against which new therapies will be evaluated during the coming decade 60. Future challenges are focused on overcoming resistance using targeted small molecules and immunomodulation, and reduction of the late complications of therapy.

Wilms Tumor

The management of Wilms tumor (WT), the most frequent primary renal tumor of children, has progressed from a solely surgical approach with a low survival rate 61 to multi-modality treatment with excellent long-term outcomes 62, 63. Before the effectiveness of AMD 64–68 was discovered, all patients received post-operative flank or whole-abdomen RT. Subsequent demonstration of the activity of VCR 69–71 and DOX 72–77 against WT, and early awareness of the adverse effects of high-dose, hemi-abdomen RT on young children 78, 79, provided the basis for refinement of therapy (Table III).

Table III. Evolution of Therapy for Wilms Tumor
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
1960197019801990Post-2000
  1. mo, months.

Chemotherapy agentsIntroduction of actinomycin D and vincristineIntroduction of doxorubicin Introduction of cyclophosphamide to regimen for patients with unfavorable histologyIntroduction of etoposide and carboplatin to regimens for patients with loss of heterozygosity for 1p and 16qVincristine
      Actinomycin D
      Doxorubicin
Dose-intensity/durationSingle agents onlyCombination of vincristine and actinomycin D; vincristine, actinomycin D and doxorubicin evaluated; Single-dose administration of actinomycin D and doxorubicin Single-dose administration of actinomycin D and doxorubicin
  15 months for group II–IV 6 months of chemotherapy adequate for all patients 6 months of chemotherapy adequate for all patients
  6 months for group I    
RadiationHigh-dose abdominal radiationAge-adjusted abdominal radiation doses crossing midlineLower dose of abdominal radiation, not age-adjusted, used in patients with stage II, III and IV diseaseLower dose of abdominal radiation, not age-adjusted, used in patients with stage III and IV disease Lower dose of abdominal radiation, not age-adjusted used in patients with stage III and IV disease
    Flank spill stage II criterion  
Flank Dose 0 to ≤18 mo: 18–24 GyStage II randomized between 0 and 20 Gy10.8 Gy for local stage III 10.8 Gy for local stage III
  19 to ≤30 mo: 24–30 GyStage II and IV randomized between 10 and 20 Gy   
  31 to ≤40 mo: 30–35 Gy    
  >40 mo: 35–40 Gy    

The initial randomized trials of the National Wilms Tumor Study (NWTS) Group, conducted between 1969 and 1978, employed age-adjusted abdominal RT doses 80, 81. Contemporary patients receive the lower doses (10.8 Gy) evaluated in NWTS-3 (1979–1986) 82. The benefit of combination chemotherapy with VCR and AMD was confirmed in NWTS-1, which randomly assigned patients to VCR or AMD only or to combination treatment 80. In NWTS-2, the relapse rate was lower among patients treated with the VCR, AMD, and DOX combination than among those treated with only VCR and AMD. This three-drug regimen included a cumulative DOX dose of 300 mg/m2 81. Contemporary patients treated with DOX, VCR, and AMD receive a lower cumulative dose of anthracycline (150 mg/m2), which was shown in NWTS-4 (1986–1994) to produce relapse-free survival rates equivalent to those obtained with 300 mg/m2 62, 63.

Treatment intensification based on loss of heterozygosity at 1p and 16q is being evaluated in current studies 83. The number of children who receive abdominal RT has decreased substantially, and some patients treated with anthracyclines since 1994 have received the lower cumulative doses prescribed in contemporary regimens. Therefore, evaluation of outcomes of patients treated during the past three decades should provide information about the late effects resulting from more widespread adoption of trial-validated regimens and will serve as the baseline for comparison of the anticipated reduction of late morbidity after reduced-intensity treatment.

Rhabdomyosarcoma

Rhabdomyosarcoma is the most frequent histological subtype among children and adolescents with soft tissue sarcomas. Before the discovery of effective chemotherapy, surgery and RT alone were curative in approximately one-third of children with rhabdomyosarcoma (RMS) 84. In the 1960s, VCR 70, 85, AMD 64, 65, and CTX 86 were shown to produce tumor responses in childhood RMS. Studies combining these three agents quickly followed 87–89. Today, VA (VCR and AMD) and VAC (VCR, AMD, and CTX), the standard chemotherapy regimens for childhood RMS in the US, cure 70% of patients (Table IV) 90. Similar outcomes have been achieved in Europe with VA or IVA (IFOS and VA) 91. Although chemotherapy dose intensification played a role, advances in pathologic classification, diagnostic imaging, surgical techniques, RT treatment planning and delivery, and supportive care contributed to this improved outcome.

Table IV. Evolution of Therapy for Rhabdomyosarcoma
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
1960197019801990Post-2000
Features used for risk stratification and treatment assignment Clinical groupClinical groupClinical groupClinical groupClinical group
     StageStage
     HistologyHistology
Chemotherapy agentsIntroduction of vincristine, actinomycin D, and cyclophosphamideIntroduction of doxorubicinIntroduction of ifosfamide and etoposideElimination of intrathecal chemotherapy for high-risk parameningeal tumorsIntroduction of irinotecanVincristine
  Introduction of intrathecal chemotherapy for high-risk parameningeal tumors   Actinomycin D
      Cyclophosphamide
Dose-intensity/durationSingle agents and small pilots of combination therapy2 years of therapy for all patients1 year of therapy for lower-risk patients1 year of therapy for all patients1 year of therapy for all patients (6 months of therapy being tested for low-risk patients)1 year of therapy
   2 years of therapy for higher-risk patientsFurther dose intensification of alkylating agentsAlkylating agent dose reductions for low- and intermediate-risk patients 
   Dose intensification of all agents Chemotherapy dose compression for high-risk patients 
Primary site radiation50–60 Gy50–60 Gy40–50 GyElimination of RT for stage 1/2, group I embryonal tumorsElimination of RT for all embryonal, group I tumors36 Gy for alveolar, group I and all group II, N0 tumors
  Introduction of early (day 0) craniospinal RT for high-risk parameningeal tumorsElimination of spinal RT for high-risk parameningeal tumors41.4 Gy for stage 3, group I and all group II tumors36 Gy for alveolar, group I and all group II, N0 tumors41.4 Gy for all group II, N1 tumors
    50.4 Gy for group III tumors41.4 Gy for all group II, N1 tumors45 Gy for group III orbit
    Elimination of cranial RT but continued early primary site RT for high-risk parameningeal tumors45 Gy for group III orbit50.4 Gy for group III non-orbit (reduction to 36 Gy after delayed wide resection, 41.4 Gy after delayed marginal resection)
     50.4 Gy for group III non-orbit (reduction to 36 Gy after delayed wide resection, 41.4 Gy after delayed marginal resection) 
Metastatic site radiation50–60 Gy for extra-pulmonary metastases50–60 Gy for extra-pulmonary metastases50–55 Gy for extra-pulmonary metastases50.4 Gy for extra-pulmonary metastases50.4 Gy for gross disease50.4 Gy for gross disease
  18 Gy whole lung RT for lung metastases18 Gy whole lung RT for lung metastases14.4 Gy whole lung RT for lung metastases36 Gy for microscopic residual disease or complete response to chemotherapy36 Gy for microscopic residual disease or complete response to chemotherapy
     0 Gy for resection with no microscopic residual0 Gy for resection with no microscopic residual
     15 Gy whole lung RT for lung metastases15 Gy whole lung RT for lung metastases

Efforts to improve systemic therapy focused on dose intensification and the introduction of new agents. The relatively low-dose, protracted VAC regimen employed in the Intergroup Rhabdomyosarcoma Study (IRS) Group, IRS-I study 92 was modified to the more dose-intensive, repetitive-pulse VAC regimen introduced in IRS-II. Doses of AMD were recently reduced in an effort to reduce the risk of hepatopathy 93–95. Many novel agents have been tested in patients with childhood RMS, including doxorubicin 96, CDDP 94, 97, VP16 94, 97, dacarbazine 94, IFOS 96, 98, melphalan 98, topotecan 99, 100, and irinotecan 101, but none has improved the outcome of low- and intermediate-risk RMS.

Local control approaches have also evolved. Definitive RT for unresected tumors uses doses ≥50 Gy with modern conformal techniques; patients who undergo initial wide or marginal tumor resection now receive lower doses (36–41.4 Gy) or may forgo RT altogether (embryonal histology group I) 102. The International Society of Pediatric Oncology (SIOP), Malignant Mesenchymal Tumor (MMT) studies, and recent Children's Oncology Group (COG) studies for low- and intermediate-risk RMS have evaluated RT dose reduction in patients with a favorable therapy response and/or favorable second-look surgery 91.

In the 1970s, ablative surgical approaches (e.g., anterior pelvic exenteration) were employed to achieve tumor control 103. The recognition that RT could produce high rates of local tumor control led to the use of more conservative surgery in the 1980s and 1990s 104. Recently, more aggressive surgery has been performed in some clinical settings to avoid the long-term adverse effects of RT 105, 106.

Therapy for children with parameningeal RMS (approximately 10% of cases) 107 has changed significantly over the years 108–110. Patients with parameningeal RMS treated on IRS-I were at significant risk of meningeal tumor dissemination when the tumor eroded the skull base, extended intracranially, or produced cranial nerve palsy. Although treatment of these patients was intensified on IRS-II through early CSI and intrathecal chemotherapy, these interventions were subsequently eliminated when local control was improved by higher chemotherapy dose intensity and better adherence to RT treatment guidelines. Early RT of the primary tumor is the standard approach.

Systemic therapy for childhood RMS has changed very little over the past few decades. VA, VAC, and IVA are the regimens most frequently utilized for treatment of patients with low- and intermediate-risk disease, and dosages are similar to those employed since the late 1970s. Patients with high-risk disease receive additional agents such as DOX, IFOS, VP16, and irinotecan, which have been evaluated in clinical trials over the past 40 years. Local control therapies have undergone minor changes. Although RT is reserved for a smaller subset of patients, the doses are similar in most cases, and differences in dose are too small to significantly alter late effects. Growing awareness of the substantial long-term toxicity of RT is raising the possibility of more aggressive surgical interventions to avoid RT.

Osteosarcoma

Successful treatment for osteosarcoma (OS), the most frequent primary malignant bone tumor of children and adolescents, requires effective systemic chemotherapy and surgical resection of all clinically detectable disease. Before the introduction of systemic chemotherapy, patients with non-metastatic OS of the extremity underwent immediate surgical resection of the primary tumor which yielded 5-year survival rates of 11–25% 111. During the early 1970s, single agents, including high-dose methotrexate (HDMTX) with leucovorin rescue 111, CDDP 111, and DOX 74, 111 were evaluated. Several studies found that single-agent or combination chemotherapy after primary tumor resection improved survival as compared to that of historical controls (Table V) 111. Other reports suggested that the apparent improvement in outcome was attributable to improved diagnosis and surgery rather than adjuvant chemotherapy 112, 113, but two randomized prospective trials subsequently confirmed the benefit of adjuvant chemotherapy 114, 115. Single institution, non-randomized trials evaluating DOX and HDMTX or DOX and CDDP regimens after primary tumor resection reported 3–5 years EFS of 50–60% or more in patients without clinically detectable metastases 111, 116–118. During the 1980s, several studies established the activity of IFOS or IFOS and VP16 for recurrent and metastatic OS 119, 120.

Table V. Evolution of Therapy for Osteosarcoma
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
1960197019801990Post 2000
  1. HDMTX, high dose methotrexate.

Chemotherapy approachNonePhase IIAdjuvantNeoadjuvantNeoadjuvantNeoadjuvant
 Single agentNeoadjuvantCombinationCombinationCombination
  Combination   
Chemotherapy agents Cisplatin,Cisplatin/DoxorubicinCisplatin/DoxorubicinCisplatin/DoxorubicinCisplatinum
 DoxorubicinCisplatin/Doxorubicin/Cisplatin/Doxorubicin/HDMTXCisplatin/Doxorubicin/HDMTXDoxorubicin
 HDMTXHDMTXCisplatin/Doxorubicin/HDMTX/IfosfamideCisplatin/Doxorubicin/HDMTX/IfosfamideHDMTX
  Phase IIClinical trial: Chemo +/- muramyl tripeptideClinical trial: Tailoring based on necrosis following neoadjuvant chemo 
  Ifosfamide (+/- Etoposide)   
Dose intensity/duration Phase II9–12 months9–12 months9–12 months9–12 months
Surgery for primary tumorAmputationAmputationLimb preservationLimb preservationLimb preservationLimb preservation
 Limb preservationAmputationAmputationAmputationAmputation
Surgery for pulmonary metastasesThoracotomyThoracotomyThoracotomyThoracotomyThoracotomyThoracotomy

Initial chemotherapy followed by definitive surgical resection rather than immediate amputation was investigated in the 1970s 121, 122. A randomized study comparing this strategy to immediate definitive surgery followed by adjuvant therapy revealed no difference in survival 123. Initial chemotherapy permits evaluation of primary tumor necrosis at the time of definitive surgical resection and was associated with improved EFS and overall survival. Clinical trials of combinations of agents with demonstrated activity (DOX, CDDP, HDMTX, and IFOS with or without VP16) from 1990 to the present reported 60–70% EFS for localized OS and identified no clearly best combination 124–127. A COG randomized trial investigating the addition of IFOS to CDDP, HDMTX, and DOX reported identical results for both treatment arms 127, 128. The same trial found that EFS and survival were improved for both localized and metastatic OS when liposomal muramyl tripeptide (L-MTP) was added to combination chemotherapy 127–129. However, the analysis was complicated by what appeared to be an interaction between the addition of IFOS and the addition of L-MTP 130. L-MTP was denied approval by the United States Food and Drug Administration in 2007, but was licensed by the European Medicines Agency in 2009. As a result the addition of L-MTP to treatment regimens for osteosarcoma remains investigational in the US.

Current treatment of OS includes initial multi-agent chemotherapy, using chemotherapy regimens developed during the 1980s, followed by definitive surgical resection of clinically detectable disease and subsequent adjuvant chemotherapy.

Ewing Sarcoma

Before the discovery of active chemotherapeutic agents, both surgery and RT were used for local control of Ewing sarcoma (ES); RT was regarded as the standard modality (Table VI). In the 1960s, after the discovery that ES responded to VCR 69, 85, CTX 131, and AMD 132, these agents were combined in multi-drug regimens, 133, 134 usually with RT 135, 136. Although long-term disease control was accomplished, investigators soon realized that combined-modality therapy increased the risk of second malignancies 137.

Table VI. Evolution of Therapy for Ewing Sarcoma
Treatment modalityDecadeHistoric treatment modalities used in contemporary therapy
1960197019801990Post-2000
  1. PTV1, planning target volume 1; PTV2, planning target volume 2.

Chemotherapy approachOften single agents, early use of combination therapyStandardized use of combination therapyCombination therapyINT-0091(1988–93) established that IE improved outcomeStandard 5-drug therapy 
Recognition of activity of doxorubicinIntroduction of ifosfamide and etoposideActinomycin D abandonedAEWS0031 showed dose compression improved outcome 
Chemotherapy agentsVincristineVincristineVincristineVincristineVincristineVincristine
CyclophosphamideCyclophosphamideCyclophosphamideCyclophosphamideCyclophosphamideCyclophosphamide
ActinomycinActinomycin DActinomycin DDoxorubicinDoxorubicinDoxorubicin
DoxorubicinDoxorubicinDoxorubicinIfosfamideIfosfamideIfosfamide
  IfosfamideEtoposideEtoposideEtoposide
  Etoposide   
Chemotherapy intensity/durationVariable, 32 weeks in MD Anderson trialsIESS-I: 89 weeksINT-0091:INT-0154:AEWS0031:29 weeks
IESS-II: 79 weeks49 weeks in both armsReg A: 48 weeksReg A: 42 weeks 
  Reg B: 30 weeksReg B: 29 weeks 
Radiation doseHigh dose, up to 60 Gy55 GyBoth irradiation and surgery permittedBoth irradiation and surgery permittedBoth irradiation and surgery permitted, but surgery preferredBoth irradiation and surgery permitted, but surgery preferred
  Most patients on IESS-I and - II had irradiation for local control45 Gy to initial disease + 3 cm margin boost to post-induction mass to 55.8 GySurgery recommended for patients responding to induction chemotherapyPTV1—45 GyPTV1—45 Gy
    45 Gy to initial disease + 2 cm margin; boost to post-induction mass to 55.8 GyPRV2—55.8 GyPRV2—55.8 Gy

In the 1970s, several single-institution studies reported that the addition of DOX to chemotherapy improved outcome 138. These studies used 60–70 Gy to the primary tumor plus combination chemotherapy with CTX (2,400 mg/m2/cycle × 5 cycles), VCR, DOX (60 mg/m2/cycle × 5 cycles), and AMD 139 or high-dose local radiation (65 Gy) plus multi-agent chemotherapy (VCR, CTX 300 mg/m2/day up to 10 daily doses) for as many as five therapy pulses 140. The first Intergroup Ewing Sarcoma Study (IESS) (IESS-I; 1973–1978), comparing VAC, VAC with whole-lung irradiation, and VAC and DOX (VAC-Adria), showed that addition of doxorubicin improved EFS. This four-drug regimen became the standard against which the efficacy of therapy modifications was measured 141. The IESS-I trial used RT doses ≤65 Gy for local control 142. The second IESS study (1978–1982) compared two different schedules of four-drug therapy and demonstrated improved overall outcome on the high-dose, intermittent schedule 143.

In the 1980s, IFOS was found to have significant activity against recurrent ES 144. When given in combination with VP16, IFOS showed substantial activity against recurrent 120 and previously untreated 145 disease. Sequential POG-Children's Cancer Group (CCG) intergroup studies demonstrated improvement in 5-year EFS among those who received VAC-Adria plus IFOS and VP16 compared to those who received only VAC-Adria 146 and no statistically significant difference in 5-year EFS between those who received standard (48 weeks) compared to intensified (30 weeks) treatment with VAC-Adria plus IFOS and VP16 147. IE did not improve the outcome of patients with metastatic disease 146. The standard and intensified arms used similar cumulative doses of doxorubicin (375 mg/m2), VCR, and IFOS (72 g/m2), but different doses of CTX (standard-10.8 g/m2 vs. intensified-12 g/m2) and VP16 (standard-4 g/m2 vs. intensified-5 g/m2) 147. In the trial comparing standard and intensified regimens, 12 patients developed secondary leukemia and seven developed secondary solid tumors 147. These two studies demonstrated that a shorter, more intensified treatment regimen produced similar EFS without increasing the risk of acute toxicity or second malignant neoplasms.

The approach to local control has evolved because of both the short- and long-term adverse effects of RT and improved surgical techniques. In early studies, radical RT (recommended dose ≤65 Gy) was the primary treatment 141, 148. However, investigators recognized the risk of permanent growth arrest and second neoplasms 137. With the development of techniques that allow preservation of function and integrated approaches for the skeletally immature child, surgical resection has been utilized more frequently for local control without compromising outcome. Most studies have shown a survival advantage for patients whose treatment included primary tumor resection 149–151. In recent studies, surgery has been used for local control in at least two-thirds of patients with non-metastatic ES 147.

The most recent COG trial of therapy for non-metastatic ES (AEWS0031) demonstrated that dose-compressed therapy given every 2 weeks was more effective and less toxic than therapy given every 3 weeks (5-year EFS 73% (every 2 weeks) vs. 65% (every 3 weeks); P = 0.048) 152. Patients older than 18 years of age at diagnosis had a significantly poorer outcome than those who were younger (5-year EFS 48% (≥18 years of age at diagnosis) vs. 72% (<18 years of age at diagnosis); P < 0.001) 152. This dose-compressed therapy prescribes substantial cumulative doses, including DOX (375 mg/m2), CTX (8.4 g/m2), IFOS (63 g/m2), and VP16 (3.5 g/m2). These agents have been utilized in combination chemotherapy for ES since 1988, and combination chemotherapy with VCR, DOX and CTX has been employed since 1972. Thus, the risk of late effects in contemporary patients treated for ES can be derived directly from historical cohorts.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISCUSSION
  5. REFERENCES
  6. Supporting Information

This review demonstrates that contemporary regimens for pediatric solid tumors prescribe many of the same agents and modalities used historically. Some historical chemotherapeutic agents and combinations have particular application to contemporary treatment protocols. The VA combination remains the primary adjuvant treatment for many children with WT and low-risk RMS. Anthracyclines remain a key component of treatment protocols for OS and ES. The use of RT for pediatric solid tumors has declined during this time because of the recognition that RT produces long-term adverse effects on normal tissues. RT is no longer given to children with stage I or II favorable-histology WT and is delayed or not used in the treatment of many children with bilateral RB. RT treatment volumes have been reduced, and surgical resection has been employed more frequently for the treatment of patients with ES. Surgery for OS has evolved from universal amputation to limb-sparing procedures for most patients. By contrast, the combination chemotherapy regimens for ES, metastatic neuroblastoma, and medulloblastoma are more intensive than those used in the past but employ most of the same agents.

The therapeutic approaches for pediatric solid tumors have evolved with the goal of improving disease-free survival while minimizing treatment-related morbidity. These changes are largely refinements of treatment protocols whose agents and modalities have been available for more than 30 years. Investigation of long-term outcomes has been instrumental in identifying childhood cancer survivor populations at high risk of specific organ toxicity and secondary carcinogenesis. This knowledge has been essential in anticipating health risks among survivors and facilitating their access to preventive and/or remedial interventions that can optimize their quality of life after childhood cancer. Treatment will continue to evolve as new agents and technologies become available; these changes will likely be slowly integrated into the highly effective contemporary regimens that allow the vast majority of children with solid tumors to become long-term survivors. Demonstration of the long-term adverse effects of historic therapy will therefore continue to play a crucial role in defining optimal therapy for these diseases.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISCUSSION
  5. REFERENCES
  6. Supporting Information
  • 1
    Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations), based on November 2011 SEER data submission, posted to the SEER web site, April 2012. Bethesda, MD: National Cancer Institute 2012.
  • 2
    Hudson MM, Neglia JP, Woods WG, et al. Lessons from the past: Opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies. Pediatr Blood Cancer 2012;58:334343.
  • 3
    Wisoff JH, Sanford RA, Heier LA, et al. Primary neurosurgery for pediatric low-grade gliomas: A prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 2011;68:15481555.
  • 4
    Bataini JP, Delanian S, Ponvert D. Chiasmal gliomas: Results of irradiation management in 57 patients and review of literature. Int J Radiat Oncol Biol Phys 1991;21:615623.
  • 5
    Merchant TE, Kun LE, Wu S, et al. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009;27:35983604.
  • 6
    Packer RJ. Chemotherapy: Low-grade gliomas of the hypthalamus and thalamus. Pediatr Neurosurg 2000;32:259263.
  • 7
    Kestle JR, J HH, R MA. Moyamoya phenomenon after radiation for optic glioma. J Neurosurg 1993;79:3235.
  • 8
    Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997;86:747754.
  • 9
    Fouladi M, Wallace D, Langston JW, et al. Survival and functional outcome of children with hypothalamic/chiasmatic tumors. Cancer 2003;97:10841092.
  • 10
    Chang CH, Housepian EM, Herbert C, Jr. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 1969;93:13511359.
  • 11
    Thomas PRM, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: Final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 2000;18:30043011.
  • 12
    Bailey CC, Gnekow A, Wellek S, et al. Prospective randomised trial of chemotherapy given before radiotherappy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 1995;25:166178.
  • 13
    Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 1999;17:21272136.
  • 14
    Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 2006;24:42024208.
  • 15
    Fouladi M, Chintagumpala M, Ashley D, et al. Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma. J Clin Oncol 2008;26:37493755.
  • 16
    Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St. Jude Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol 2006;7:813820.
  • 17
    Jakacki RI. Treatment strategies for high-risk medulloblastoma and supratentorial primitive neuroectodermal tumors. Review of the literature. J Neurosurg 2005;102:4452.
  • 18
    Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993;328:17251731.
  • 19
    Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: A report from the Children's Cancer Group. J Clin Oncol 2005;23:76217631.
  • 20
    Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005;352:978986.
  • 21
    Ridola V, Grill J, Doz F, et al. High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy. Cancer 2007;110:156163.
  • 22
    Hukin J, Epstein F, Lefton D, et al. Treatment of intracranial ependymoma by surgery alone. Pediatr Neurosurg 1998;29:4045.
  • 23
    Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: A prospective study. Lancet Oncol 2009;10:258266.
  • 24
    Conklin HM, Li C, Xiong X, et al. Predicting change in academic abilities after conformal radiation therapy for localized ependymoma. J Clin Oncol 2008;26:39653970.
  • 25
    Clark RD, Mansfield NC. Retinoblastoma: Genetic testing and counseling. In: Singh AD, Damato BE, Pe'er J, et al., editors. Clinical ophthalmic oncology. Philadelphia: Saunders Elsevier; 2007. pp 441446.
  • 26
    Kleinerman RA, Yu CL, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol 2012;30:950957.
  • 27
    Knudson AGJ. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820823.
  • 28
    Rodriguez-Galindo C, Meadows AT. Retinoblastoma. In: Carroll WL, Finlay JL, editors. Cancer in children: The clinical biology of childhood cancer. Sudbury MA: Jones and Bartlett Publishers; 2010. pp 437457.
  • 29
    Murphree AT. Local therapy, brachytherapy and enucleation. In: Singh AD, Damato BE, Pe'er J, et al., editors. Clinical opththalmic oncology. Philadelphia: Sanders Elsevier; 2007. 454461.
  • 30
    Young JL, Smith MA, Roffers SD, et al. Retinoblastoma. In: Ries LAG, Smith MA, Gurney JG, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute, SEER Program; 1999. 7378.
  • 31
    Rubin CM, Robison LL, Cameron JD, et al. Intraocular retinoblastoma group V: An analysis of prognostic factors. J Clin Oncol 1985;3:680685.
  • 32
    Hungerford JL, Toma NMG, Plowman PN, et al. External beam radiotherapy for retinoblastoma: I. Whole eye technique. Br J Ophthalmol 1995;79:109111.
  • 33
    Wilson MW, Haik BG, Liu T, et al. Effect on ocular survival of adding early intensive focal treatments to a two-drug chemotherapy regimen in patients with retinoblastoma. Am J Ophthalmol 2001;140:397406.
  • 34
    Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000;18:1217.
  • 35
    Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 2003;21:20192025.
  • 36
    Shields CL, Shields JA, Cater J, et al. Plaque radiotherapy for retinoblastoma. Long-term control and treatment complications in 208 tumors Ophthalmology 2001;108:21162121.
  • 37
    Chong EM, Coffee RE, Chintagumpala M, et al. Extensively necrotic retinoblastoma is associated with high-risk prognostic factors. Arch Pathol Lab Med 2006;130:16691672.
  • 38
    Rodriguez-Galindo C, Chantada GL, Haik BG, et al. Treatment of retinoblastoma: Current status and future perspectives. Curr Treat Options Neurol 2007;9:294307.
  • 39
    Hayden BH, Murray TG, Scott IU, et al. Subconjunctival carboplatin in retinoblastoma. Impact of tumor burden and dose schedule. Arch Ophthalmol 2000;118:15491554.
  • 40
    Krasin MJ, Crawford BT, Zhu Y, et al. Intensity-modulated radiation therapy for children with intraocular retinoblastoma; potential sparing of the bony orbit. Clin Oncol (Roy Coll Radiol) 2004;16:215222.
  • 41
    Krengli M, Hug EB, Adams JA, et al. Proton radiation therapy for retinoblastoma: Comparison of various intraocular tumor locations and beam arrangements. Int J Radiat Oncol Biol Phys 2005;61:583593.
  • 42
    Dunkel IJ, Aledo A, Kernan NA, et al. Successful treatment of metastatic retinoblastoma. Cancer 2000;89:21172121.
  • 43
    Kremens B, Wieland R, Reinhard H, et al. High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 2003;31:281284.
  • 44
    Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment of metastatic retinoblastoma. Ophthalmology 2003;110:12371240.
  • 45
    Finklestein JZ, Hittle RE, Hammond GD. Evaluation of a high dose cyclophosphamide regimen in childhood tumors. Cancer 1969;23:12391242.
  • 46
    Leikin S, Bernstein I, Evans A, et al. Use of combination adriamycin (NSC-123127) and DTIC (NSC-45388) in children with advanced stage IV neuroblastoma. Cancer Chemother Rep 1975;59:10151018.
  • 47
    Nitschke R, Starling KA, Vats T, et al. Cis-diamminedichloroplatinum (NSC-119875) in childhood malignancies: A Southwest Oncology Group study. Med Pediatr Oncol 1978;4:127132.
  • 48
    Rivera G, Green A, Hayes A, et al. Epipodophyllotoxin VM-26 in the treatment of childhood neuroblastoma. Cancer Treat Rep 1977;61:12431248.
  • 49
    Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 1989;7:236244.
  • 50
    Evans AE, Brand W, de Lorimier A, et al. Results in children with local and regional neuroblastoma managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide. A report from the Children's Cancer Study Group. Am J Clin Oncol 1984;7:37.
  • 51
    Jacobson G, Sause W, O'Brien R. Dose response analysis of pediatric neuroblastoma to megavoltage radiation. Am J Clin Oncol 1984;7:693697.
  • 52
    Matthay KK, Yanik G, Messina J, et al. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 2007;25:10541060.
  • 53
    Hartmann O, Pinkerton CR, Philip T, et al. Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. J Clin Oncol 1988;6:4450.
  • 54
    Castello MA, Clerico A, Jenkner A, et al. A pilot study of high-dose carboplatin and pulsed etoposide in the treatment of childhood solid tumors. Pediatr Hematol Oncol 1990;7:129135.
  • 55
    Hartmann O, Benhamou E, Beaujean F, et al. High-dose busulfan and cyclophosphamide with autologous bone marrow transplantation support in advanced malignancies in children: A phase II study. J Clin Oncol 1986;4:18041810.
  • 56
    Cheung NK, Landmeier B, Neely J, et al. Complete tumor ablation with iodine 131-radiolabeled disialoganglioside GD2-specific monoclonal antibody against human neuroblastoma xenografted in nude mice. J Natl Cancer Inst 1986;77:739745.
  • 57
    Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 1999;341:11651173.
  • 58
    Gilman AL, Ozkaynak MF, Matthay KK, et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: A report from the Children's Oncology Group. J Clin Oncol 2009;27:8591.
  • 59
    Matthay KK, Tan JC, Villablanca JG, et al. Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: A new approaches to Neuroblastoma Therapy Consortium study. J Clin Oncol 2006;24:500506.
  • 60
    Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010;363:13241334.
  • 61
    Green DM, Jaffe N. The role of chemotherapy in the treatment of Wilms' tumor. Cancer 1979;44:5257.
  • 62
    Green DM, Breslow NE, Beckwith JB, et al. Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:237245.
  • 63
    Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:37443751.
  • 64
    Tan CTC, Dargeon HW, Burchenal JH. The effect of actinomycin D on cancer in childhood. Pediatrics 1959;24:544561.
  • 65
    Pinkel D. Actinomycin D in childhood cancer. A preliminary report. Pediatrics 1959;23:342347.
  • 66
    Shaw RK, Moore EW, Mueller PS, et al. The effect of actinomycin D on childhood neoplasms. AMA J Dis Child 1960;99:628635.
  • 67
    Sutow WW. Chemotherapy in childhood cancer (except leukemia). Cancer 1968;18:15851589.
  • 68
    Farber S, editor. Clinical and biological studies with actinomycins. Boston: Little Brown and Company; 1958.
  • 69
    James DHJ, George P. Vincristine in children with malignant solid tumors. J Pediatr 1964;64:534541.
  • 70
    Selawry OS, Holland JF, Wolman IJ. Effect of vincristine (NSC 67574) on malignant solid tumors in children. Cancer Chemother Rep 1968;52:497500.
  • 71
    Sutow WW, Thurman WG, Windmiller J. Vincristine (leurocristine) sulfate in the treatment of children with metastatic Wilms' tumor. Pediatrics 1963;32:880887.
  • 72
    Bonnadonna G, Beretta G, Tancini G, et al. Adriamycin (NSC 123127) studies at the Istituto Nazionale Tumori, Milan. Cancer Chemo Rep 1975;6:231245.
  • 73
    Evans AE, Baehner RL, Chard RLJ, et al. Comparison of daunorubicin (NSC 83142) with Adriamycin (NSC 123127) in the treatment of late stage childhood solid tumors. Cancer Chemother Rep 1974;58:671676.
  • 74
    Pratt CB, Shanks EC. Doxorubicin in treatment of malignant solid tumors in children. Am J Dis Child 1974;127:534536.
  • 75
    Ragab AH, Sutow WW, Komp DM, et al. Adriamycin in the treatment of childhood solid tumors. Cancer 1975;36:15671571.
  • 76
    Tan C, Rosen G, Ghavimi F, et al. Adriamycin (NSC 123127) in pediatric malignancies. Cancer Chemother Rep 1975;6:259266.
  • 77
    Wang JJ, Holland JF, Sinks LF. Phase II study of Adriamycin (NSC 123127) in childhood solid tumors. Cancer Chemother Rep 1975;6:267270.
  • 78
    Neuhauser EBD, Wittenborg MH, Berman CZ, et al. Irradiation effects of roentgen therapy on the growing spine. Radiology 1952;59:637650.
  • 79
    Rubin P, Duthie RB, Young LW. The significance of scoliosis in postirradiated Wilms's tumor and neuroblastoma. Radiology 1962;79:539559.
  • 80
    D'Angio GJ, Evans AE, Breslow N, et al. The treatment of Wilms' tumor: Results of the National Wilms' Tumor Study. Cancer 1976;38:633646.
  • 81
    D'Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms' tumor: Results of the Second National Wilms' Tumor Study. Cancer 1981;47:23022311.
  • 82
    D'Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 1989;64:349360.
  • 83
    Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: A report from the National Wilms Tumor Study Group. J Clin Oncol 2005;23:73127321.
  • 84
    Sutow WW, Sullivan MP, Ried HL, et al. Prognosis in childhood rhabdomyosarcoma. Cancer 1970;25:13841390.
  • 85
    Sutow WW. Vincristine (NSC-67574) therapy for malignant solid tumors in children (except Wilms' tumor). Cancer Chemother Rep 1968;52:485487.
  • 86
    Steinberg J, Haddy TB, Porter FS, et al. Clinical trials with cyclophosphamide in children with soft tissue sarcoma. Cancer Chemother Rep 1963;28:3941.
  • 87
    Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomyosarcoma of head and neck in children. Combination treatment by surgery, irradiation, and chemotherapy. Cancer 1973;31:2635.
  • 88
    James DHJ, Hustu O, Wrenn ELJ, et al. Childhood malignant tumors. Concurrent chemotherapy with dactinomycin and vincristine sulfate. JAMA 1966;197:10431045.
  • 89
    Wilbur JR. Combination chemotherapy for embryonal rhabdomyosarcoma. Cancer Chemother Rep 1974;58:281284.
  • 90
    Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 2001;19:30913102.
  • 91
    Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: Third study of the International Society of Paediatric Oncology-SIOP malignant mesenchymal tumor 89. J Clin Oncol 2005;23:26182628.
  • 92
    Maurer HM, Beltangady M, Gehan EA, et al. The intergroup rhabdomyosarcoma study-I. A final report. Cancer 1988;61:209220.
  • 93
    Maurer HM, Gehan EA, Beltangady M, et al. The intergroup rhabdomyosarcoma study-II. Cancer 1993;71:19041922.
  • 94
    Crist W, Gehan EA, Ragab AH, et al. The third intergroup rhabdomyosarcoma study. J Clin Oncol 1995;13:610630.
  • 95
    Spunt S, Smith LM, Ruymann FB, et al. Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Clin Cancer Res 2004;10:60726079.
  • 96
    Sandler E, Lyden E, Ruymann F, et al. Efficacy of ifosfamide and doxorubicin given as a phase II “window” in children with newly diagnosed metastatic rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 2001;37:442448.
  • 97
    Crist WM, Raney RB, Ragab A, et al. Intensive chemotherapy including cisplatin with or without etoposide for children with soft-tissue sarcomas. Med Pediatr Oncol 1987;15:5157.
  • 98
    Breitfeld PP, Lyden E, Raney RB, et al. Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: A report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 2001;23:225233.
  • 99
    Pappo AS, Lyden E, Breneman J, et al. Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An Intergroup Rhabdomyosarcoma Study. J Clin Oncol 2001;19:213219.
  • 100
    Walterhouse DO, Lyden ER, Breitfeld PP, et al. Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: A Children's Oncology Group study. J Clin Oncol 2004;22:13981403.
  • 101
    Pappo AS, Lyden E, Breitfeld P, et al. Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: The Children's Oncology Group. J Clin Oncol 2007;25:362369.
  • 102
    Wolden SL, Anderson JR, Crist WM, et al. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 1999;17:34683475.
  • 103
    Hays DM, Raney RBJ, Lawrence WJ, et al. Primary chemotherapy in the treatment of children with bladder-prostate tumors in the Intergroup Rhabdomyosarcoma Study (IRS-II). J Pediatr Surg 1982;17:812820.
  • 104
    Lobe TE, Wiener E, Andrassy RJ, et al. The argument for conservative, delayed surgery in the management of prostatic rhabdomyosarcoma. J Pediatr Surg 1996;31:10841087.
  • 105
    Arndt C, Rodeberg D, Breitfeld PP, et al. Does bladder preservation (as a surgical principle) lead to retaining bladder function in bladder/prostate rhabdomyosarcoma? Results from Intergroup Rhabdomyosarcoma Study IV. J Urol 2004;171:23962403.
  • 106
    Spunt SL, Sweeney TA, Hudson MM, et al. Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors. J Clin Oncol 2005;23:71437151.
  • 107
    Sultan I, Qaddoumi I, Yaser S, et al. Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program 1973 to 2005: An analysis of 2,600 patients. J Clin Oncol 2009;27:33913397.
  • 108
    Ochs JJ, Freeman AI, Douglass HO, Jr., et al. cis-Dichlorodiammineplatinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep 1978;62:239245.
  • 109
    Baum ES, Gaynon P, Greenberg L, et al. Phase II study of cis-dichlorodiammineplatinum(II) in childhood osteosarcoma: Children's Cancer Study Group Report. Cancer Treat Rep 1979;63:16211627.
  • 110
    Raney RB, Meza J, Anderson JR, et al. Treatment of children and adolescents with localized parameningeal sarcoma: Experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978–1997 Med Pediatr Oncol 2002;38:2232.
  • 111
    Anninga JK, Gelderblom H, Fiocco M, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? Eur J Cancer 2011;47:24312445.
  • 112
    Carter SK. Adjuvant chemotherapy in osteogenic sarcoma: The triumph that isn't? J Clin Oncol 1984;2:147148.
  • 113
    Taylor WF, Ivins JC, Pritchard DJ, et al. Trends and variability in survival among patients with osteosarcoma: A 7-year update. Mayo Clin Proc 1985;60:91104.
  • 114
    Eilber F, Giuliano A, Eckardt J, et al. Adjuvant chemotherapy for osteosarcoma: A randomized prospective trial. J Clin Oncol 1987;5:2126.
  • 115
    Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314:16001606.
  • 116
    Ettinger LJ, Douglass HOJ, Mindell ER, et al. Adjuvant Adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity. J Clin Oncol 1986;4:353362.
  • 117
    Goorin AM, Frei E III, Abelson HT. Adjuvant chemotherapy for osteosarcoma: A decade of experience. Surg Clin North Am 1981;61:13791389.
  • 118
    Pratt CB, Champion JE, Fleming ID, et al. Adjuvant chemotherapy for osteosarcoma of the extremity. Long-term results of two consecutive prospective protocol studies. Cancer 1990;65:439445.
  • 119
    Harris MB, Cantor AB, Goorin AM, et al. Treatment of osteosarcoma with ifosfamide: Comparison of response in pediatric patients with recurrent disease versus patients previously untreated: A Pediatric Oncology Group study. Med Pediatr Oncol 1995;24:8792.
  • 120
    Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and etoposide: An effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5:11911198.
  • 121
    Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 1979;43:21632177.
  • 122
    Rosen G, Murphy ML, Huvos AG, et al. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 1976;37:111.
  • 123
    Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003;21:15741580.
  • 124
    Bielack S, Jurgens H, Jundt G, et al. Osteosarcoma: The COSS experience. Cancer Treat Res 2009;152:289308.
  • 125
    Picci P, Mercuri M, Ferrari S, et al. Survival in high-grade osteosarcoma: Improvement over 21 years at a single institution. Ann Oncol 2010;21:13661373.
  • 126
    Petrilli AS, de Camargo B, Filho VO, et al. Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: Prognostic factors and impact on survival. J Clin Oncol 2006;24:11611168.
  • 127
    Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: A randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005;23:20042011.
  • 128
    Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group. J Clin Oncol 2008;26:633638.
  • 129
    Chou AJ, Kleinerman ES, Krailo MD, et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: A report from the Children's Oncology Group. Cancer 2009;115:53395348.
  • 130
    Bielack SS. Osteosarcoma: Time to move on? Eur J Cancer 2010;46:19421945.
  • 131
    Sutow WW, Sullivan MP. Cyclophosphamide therapy in children with Ewing's sarcoma. Cancer Chemother Rep 1962;23:5560.
  • 132
    Senyszyn JJ, Johnson RE, Curran RE. Treatment of metastatic Ewing's sarcoma with actinomycin D (NSC-3053). Cancer Chemother Rep 1970;54:103107.
  • 133
    Green DM. Evaluation of single-dose vincristine, actinomycin D, and cyclophosphamide in childhood solid tumors. Cancer Treat Rep 1978;62:15171520.
  • 134
    Pratt CB, James DHJ, Holton CP, et al. Combination therapy including vincristine (NSC-67574) for malignant solid tumors in children. Cancer Chemother Rep 1968;52:489495.
  • 135
    Hustu HO, Holton C, James DJ, et al. Treatment of Ewing's sarcoma with concurrent radiotherapy and chemotherapy. J Pediatr 1968;73:249251.
  • 136
    Hustu HO, Pinkel D, Pratt CB. Treatment of clinically localized Ewing's sarcoma with radiotherapy and combination chemotherapy. Cancer 1972;30:15221527.
  • 137
    Strong LC, Herson J, Osborne BM, et al. Risk of radiation-related subsequent malignant tumors in survivors of Ewing's sarcoma. J Natl Cancer Inst 1979;62:14011406.
  • 138
    Pomeroy TC, Johnson RE. Combined modality therapy of Ewing's sarcoma. Cancer 1975;35:3647.
  • 139
    Rosen G, Caparros B, Mosende C, et al. Curability of Ewing's sarcoma and considerations for future therapeutic trials. Cancer 1978;41:888899.
  • 140
    Suit HD, Martin RG, Sutow WW. Primary malignant tumors of the bone. In: Sutow WW, Vietti TJ, Fernbach DJ, editors. Clinical Pediatric Oncology. St. Louis: C.V. Mosby; 1973. pp 480487.
  • 141
    Nesbit MEJ, Perez CA, Tefft M, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: An Intergroup Study. Natl Cancer Inst Monogr 1981;56:255262.
  • 142
    Razek A, Perez CA, Tefft M, et al. Intergroup Ewing's sarcoma study: Local control related to radiation dose, volume, and site of primary lesion in Ewing's sarcoma. Cancer 1980;46:516521.
  • 143
    Burgert EO, Jr., Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: Intergroup study IESS-II. J Clin Oncol 1990;8:15141524.
  • 144
    Scheulen ME, Niederle N, Bremer K, et al. Efficacy of ifosfamide in refractory malignant diseases and uroprotection by mesna: Results of a clinical phase II-study with 151 patients. Cancer Treat Rev 1983;10:93101.
  • 145
    Meyer WH, Kun L, Marina N, et al. Ifosfamide plus etoposide in newly diagnosed Ewing's sarcoma of bone. J Clin Oncol 1992;10:17371742.
  • 146
    Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694701.
  • 147
    Granowetter L, Womer R, Devidas M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: A Children's Oncology Group Study. J Clin Oncol 2009;27:25362541.
  • 148
    Oldham RK, Pomeroy TC. Treatment of Ewing's sarcoma with Adriamycin (NSC-123127). Cancer Chemother Rep 1972;56:635639.
  • 149
    Bacci G, Ferrari S, Bertoni F, et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: Analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 2000;18:411.
  • 150
    Bacci G, Forni C, Longhi A, et al. Long-term outcome for patients with non-metastatic Ewing's sarcoma treated with adjuvant and neoadjuvant chemotherapies 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 2004;40:7383.
  • 151
    Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: Results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 2003;55:168177.
  • 152
    Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children's Oncology Group. J Clin Oncol 2012;30:41484154.

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. DISCUSSION
  5. REFERENCES
  6. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
pbc_24487_sm_SuppTabI.docx16KSupplementary Table I. Evolution of Therapy for Low Grade Glioma
pbc_24487_sm_SuppTabII.docx15KSupplementary Table II. Evolution of Therapy for Ependymoma
pbc_24487_sm_SuppTabIII.docx17KSupplementary Table III. Evolution of Therapy for Retinoblastoma

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