Evidence-Based Pediatric Oncology E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Evidence-Based Medicine
• Sprache: Englisch

Seitenzahl: 810

Veröffentlichungsjahr: 2013

Beschreibung

The new and updated edition of the renowned reference for pediatric oncologists

This groundbreaking text on the management of childhood cancers covers most tumor types occurring in children and young adults and provides reviews of randomized trials with commentaries on the optimum treatments for childhood cancer.

Updated with evidence from the latest published reviews—and even more clinically focused than previous editions— Evidence-Based Pediatric Oncology, Third Edition places an emphasis on application of the trial findings. With increased coverage of the area of supportive care for pediatric cancer patients, each chapter opens with an expert commentary on the key clinical issues followed by a summary of trial findings.

Evidence-Based Pediatric Oncology, Third Edition:

• Presents evidence for the best treatment of children and adolescents with cancer

• Includes commentaries from the world’s leading experts for every topic discussed

• Is internationally relevant thanks to contributions from the UK, US, Canada and Australia

• Places greater emphasis on supportive care and features a new extended section on antibiotic and antifungal treatments

Based on information gathered from randomized trials performed after the release of the Second Edition, readers will find Evidence-Based Pediatric Oncology to be an important resource for all those treating young people with cancer.

Leseprobe

Contents

List of contributors

Preface

List of abbreviations

About the companion website

PART 1: Solid tumors

CHAPTER 1: Rhabdomyosarcoma

Philosophy of treatment of rhabdomyosarcoma

Treatment: the general approach

Lessons from studies of rhabdomyosarcoma

Lessons from studies of nonrhabdomyosarcoma soft tissue sarcomas

Conclusion

Study 1

Study 2

CHAPTER 2: Osteosarcoma

Study 1

Study 2

Study 3

CHAPTER 3: Ewing sarcoma

Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

Study 7

CHAPTER 4: Wilms tumor

Study 1

Study 2

Study 3

CHAPTER 5: Neuroblastoma

Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

CHAPTER 6: Hepatoblastoma

Study 1

Study 2

CHAPTER 7: Malignant germ cell tumors

CHAPTER 8: Medulloblastoma

Early randomized studies

Recent medulloblastoma trials

Future directions

Study 1

Study 2

Study 3

CHAPTER 9: Glioma

Radiation therapy

Chemotherapy

Conclusions

CHAPTER 10: Non-Hodgkin lymphoma

Study 1

Study 2

Study 3

Study 4

CHAPTER 11: Hodgkin lymphoma

Radiation therapy

Combination therapy

Chemotherapy only

Study 1

Study 2

PART 2: Leukemia

CHAPTER 12: Acute myeloid leukemia commentary

Induction

Postremission therapy

CHAPTER 13: Remission induction in acute myeloid leukemia

Study 1

Study 2

Study 3

Study 4

CHAPTER 14: Acute myeloid leukemia consolidation

Study 1

CHAPTER 15: Maintenance treatment in acute myeloid leukemia

CHAPTER 16: Autologous bone marrow transplantation in acute myeloid leukemia

CHAPTER 17: Acute myeloid leukemia: miscellaneous

Study 1

CHAPTER 18: Childhood lymphoblastic leukemia commentary

Remission induction

Postinduction therapy

Continuation therapy

Minimal residual disease

Relapsed acute lymphoblastic leukemia

Long-term effects

New agents

CHAPTER 19: Remission induction in childhood lymphoblastic leukemia

Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

Study 7

CHAPTER 20: Central nervous system-directed therapy in childhood lymphoblastic leukemia

Dose of irradiation

The need for irradiation in central nervous system-directed therapy

Schedule of irradiation

Type of intrathecal therapy and duration of treatment

Role of intermediate- and high-dose methotrexate

Role of high-dose cytarabine

Overview

CHAPTER 21: Maintenance treatment in childhood lymphoblastic leukemia

Duration of therapy

Pulses of steroids and vincristine

Dose and route of methotrexate

Drug schedule

Type of thiopurine

Addition of other drugs during continuing therapy

Study 1

Study 2

Drug schedule

Study 3

Study 4

Study 5

Type of thiopurine

Study 6

Study 7

Study 8

Study 9

CHAPTER 22: Relapsed childhood lymphoblastic leukemia

Study 1

Study 2

Study 3

Study 4

CHAPTER 23: Postinduction therapy in adolescents and young adults with acute lymphoblastic leukemia

Study 1

Study 2

PART 3: Supportive care in pediatric oncology

CHAPTER 24: Colony-stimulating factors

Granulocyte colony-stimulating factor

Granulocyte macrophage colony-stimulating factor

Erythropoietin

Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

CHAPTER 25: Cardioprotection in pediatric oncology

Study 1

Study 2

Study 3

Efficacy of anthracyclines in pediatric oncology

Study 4

Study 5

CHAPTER 26: Infections in pediatric and adolescent oncology

Introduction

Risk stratification

Fungal infection

Central venous catheter infections

Study 1

Study 2

Study 3

Study 4

Study 5

Study 6

Study 7

Study 8

Study 9

Study 10

Study 11

Study 12

Study 13

Study 14

Study 15

Study 16

Study 17

Study 18

Study 19

Study 20

Index

This edition first published 2013 © 2002, 2007, 2013 by John Wiley & Sons, Ltd.

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Library of Congress Cataloging-in-Publication Data

Evidence-based pediatric oncology / edited by Ross Pinkerton, Ananth Shankar, Katherine K. Matthay. – 3rd ed. p. ; cm. Includes bibliographical references and index.

ISBN 978-0-470-65964-9 (hardback : alk. paper) I. Pinkerton, C. R. (C. Ross), 1950– II. Shankar, A. G. (Ananth Gouri), 1962– III. Matthay, Katherine. [DNLM: 1. Child–Case Reports. 2. Neoplasms–Case Reports. 3. Evidence-Based Medicine–Case Reports. QZ 275] 618.92′994–dc23

2012044509

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover image: High grade glioma imaged with 18Fluorine PET MRI, photo reproduced courtesy of Professor AG ShankarCover design by Andy Meaden

List of contributors

Robert J. ArceciKing Fahd Professor of Pediatric OncologyJohns Hopkins UniversityBaltimore, MD, USAJoann L. AterProfessor, Department of Pediatrics Patient CareDivision of PediatricsThe University of TexasMD Anderson Cancer CenterHouston, TX, USAEric BouffetGarron Family Chair in Childhood Cancer ResearchDirector, Paediatric Neuro-Oncology ProgramProfessor of PaediatricsHospital for Sick ChildrenToronto, ON, CanadaPenelope BrockConsultant in Paediatric OncologyGreat Ormond Street HospitalLondon, UKJulia E. ClarkConsultant in Paediatric Infectious DiseasesRoyal Children’s HospitalChildren’s Health Queensland Brisbane, QLD, AustraliaSteven G. DuBoisAssociate Professor of PediatricsUCSF School of Medicine andUCSF Benioff Children’s HospitalSan Francisco, CA, USAVictoria GrandageChildren and Young Peoples Cancer ServiceUniversity College London Hospitals NHS Foundation TrustLondon, UKMeriel JenneyConsultant Paediatric OncologistChildren’s Hospital for WalesCardiff, UKGill A. LevittConsultant in Paediatric Oncology and Late EffectsGreat Ormond Street HospitalLondon, UKKatherine K. MatthayMildred V. Strouss Professor of Translational OncologyDirector, Pediatric Hematology-OncologyDepartment of PediatricsUCSF School of Medicine andUCSF Benioff Children’s HospitalSan Francisco, CA, USAMaria MichelagnoliChildren and Young People Cancer ServiceUniversity College London Hospitals NHS Foundation TrustLondon, UKRoss PinkertonExecutive Director, Division of OncologyRoyal Children’s HospitalChildren’s Health Queensland Brisbane, QLD, AustraliaKathy Pritchard-JonesProfessor of Paediatric OncologyICH - Molecular Haematology and Cancer BiologyDepartment of CancerFaculty of Population Health SciencesUniversity College LondonLondon, UKVaskar SahaProfessor of Paediatric OncologySchool of Cancer and Enabling SciencesThe University of ManchesterManchester Academic Health Science CentreThe Christie NHS Foundation TrustManchester, UKCindy L. SchwartzAlan G. Hassenfel Professor of PediatricsThe Warren Alpert Medical School of Brown UniversityDirector of Pediatric Hematology/OncologyDepartment of PediatricsHasbro Children’s HospitalProvidence, RI, USAAnanth ShankarConsultant in Paediatric and Adolescent OncologyUniversity College London Hospitals NHS Foundation TrustLondon, UKSara StonehamPaediatric and Adolescent Consultant OncologistUniversity College London Hospitals NHS Foundation TrustLondon, UK

Preface

The aim of this book is to summarize the information that is available from published randomized trials in childhood cancer. These data should not only provide a rational evidence base for the current practice but also demonstrate particular gaps in our knowledge and indicate which new studies should be a priority.

In recent years, the rate of improvement in outcomes for children’s cancers has tended to reach a ­plateau and it has become increasingly important to design trials that ask explicit questions, are powered to be reliable, and will provide answers in a reasonable time. The high cure rates require large numbers of patients to demonstrate relatively small incremental improvement, in the case of therapeutic studies, or equivalence, where avoiding late effects through dose reduction is the goal.

Consequently, the pediatric oncology literature is littered with small single-arm “studies” and reports of what is essentially “best standard practice” which, whilst of interest, often fail to make progress.

Reluctance to run large randomized trials has resulted in the overuse of unproven strategies, sometimes with significant early and late morbidity, such as in the empirical application of very high-dose therapy with stem cell rescue in solid tumors other than neuroblastoma. It may also lead to the slow application of effective treatments.

Similarly, because of the small number of randomized trials in most childhood solid tumors, formal meta-analysis is often not possible. The Cochrane Childhood Cancer Group, set up in 2006 and based in Amsterdam, made a valiant attempt to address this issue (see www.thecochranelibrary.com for available reviews). Unfortunately, it has often been faced with a paucity of data or has had to rely on studies covering many decades during which time treatment has changed considerably and meta-analysis may, therefore, be less informative.

Much current practice is based on protocols that appear to produce the most favorable results in single-arm studies. Many are associated with significant early and late morbidity which subsequent randomized evaluation proves to have been unjustified. It is, therefore, of importance that all novel strategies are ­adequately evaluated before they become accepted as standard practice. It is hoped that the data in this book will provide ready access to background information for those involved in trial design and also be of value to those early in their oncology careers who should be aware of what studies have been done but find that most textbooks provide only minimal details of these trials.

This edition has focused on studies published since the completion of the second edition in 2007. The conclusions from the studies in the last two editions are outlined in specific sections. We have again been fortunate to have persuaded many well-known figures in children’s cancer to add short commentaries to each section. These focus on the major conclusions from the studies presented and also on future research priorities.

Ross Pinkerton2013

List of abbreviations

6-MP

6-mercaptopurine

6-TG

6-thioguanine

AA

anaplastic astrocytoma

ABMT

autologous bone marrow transplantation

ABVD

doxorubicin, bleomycin, vinblastine, dacarbazine

ABVE

doxorubicin, bleomycin, vincristine, etoposide

ABVE-PC

doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide

ACOMP

doxorubicin, cyclophosphamide, vincristine, methylprednisolone, prednisone

ACOP

doxorubicin, cyclophosphamide, vincristine, prednisone

ACT-D

actinomycin D

AE

adverse events

AFP

α-fetoprotein

ALCL

anaplastic large cell lymphoma

ALK

anaplastic lymphoma kinase

ALL

acute lymphoblastic leukemia

allo-BMT

allogeneic bone marrow transplantation

allo-SCT

allogeneic stem cell transplantation

ALPN

allopurinol

ALT

alanine aminotransferase

AML

acute myeloid leukemia

ANC

absolute neutrophil count

AOP

doxorubicin, vincristine, prednisone

AP

Adriamycin/cisplatin

APL

acute promyelocytic leukemia

APTT

activated partial thromboplastin time

ARAC

cytosine arabinoside

ASCO

American Society of Clinical Oncology

ASCT

autologous stem cell transplant

ASN

asparagine

ASP

asparaginase

AST

aspartate aminotransferase

ATRA

all-trans-retinoic acid

AVA

doxorubicin plus vincristine and actinomycin (VA)

B-ALL

B-cell acute lymphoblastic leukemia

BCD

cisplatin or bleomycin, cyclophosphamide, actinomycin D

BEP

bleomycin, etoposide, cisplatin

BFM

Berlin-Frankfurt-Münster

BL

Burkitt lymphoma

BLL

Burkitt-like lymphoma

BM

bone marrow

BMT

bone marrow transplant

BNHL

B-cell non-Hodgkin lymphoma

BuMel

busulfan and melphalan

CAA

cancer-associated anemia

CAI

catheter-associated infection

CALGB

Cancer and Leukemia Group B

cALL

common acute lymphoblastic leukemia

CC

continuation chemotherapy

CCF

congestive cardiac failure

CCR

continuous clinical remission

CCSG

Children’s Cancer Study Group

CCSK

clear cell sarcoma of kidney

CDI

chemotherapy dose intensity

CDR

clinical decision rules

CEM

melphalan, etoposide, carboplatin

CFRT

conventional fractionated radiotherapy

CHF

congestive heart failure

CHOP

cyclophosphamide, doxorubicin, vincristine, prednisone

CI

confidence interval, cumulative incidence

CLDB

cladribine

CML

chronic myeloid leukemia

CNS

central nervous system

COG

Children’s Oncology Group

COJEC

cisplatin, vincristine, carboplatin, etoposide, cyclophosphamide

COMP

cyclophosphamide, vincristine, methotrexate, prednisone

COP

cyclophosphamide, vincristine, prednisolone

COPAD

cyclophosphamide, vincristine, prednisone, doxorubicin

COPAdM

cyclophosphamide, vincristine, prednisolone, doxorubicin, and high-dose methotrexate with intrathecal methotrexate

COPP

cyclophosphamide, vincristine, prednisone, procarbazine

CR

complete remission/response

CRBSI

catheter-related bloodstream infection

CRT

cranial irradiation

CS

craniospinal

CsA

cyclosporine A

CSF

cerebrospinal fluid; colony-stimulating factor

CSRT

craniospinal radiotherapy

CT

chemotherapy; computed tomography; continuing therapy

CVC

central venous catheter

CVPP

cyclophosphamide, vincristine, procarbazine, prednisone

DA

daunorubicin and ARA-C

DAT

daunomycin, cytarabine, thioguanine

DD

divided dose

DEX

dexamethasone

DFCI

Dana-Farber Cancer Institute

DFS

disease-free survival

DI

delayed intensification

DIPG

diffuse intrinsic pontine glioma

DLBCL

diffuse large B-cell lymphoma

DLCL

diffuse large cell lymphoma

DMC

data monitoring committee

DNPS

de novo purine synthesis

DNR

daunorubicin

DT

disproportionate thrombocytopenia

ECHO

echocardiography

ECOG

Eastern Co-operative Oncology Group

EF

extended field

EFS

event-free survival

EOI

European Osteosarcoma Intergroup

EORTC

European Organization for Research into Treatment of Cancer

EPO

erythropoietin

EpSSG

European Paediatric Soft Tissue Sarcoma Group

ETPALL

early T precursor acute lymphoblastic leukemia

EVAIA

vincristine, doxorubicin, dactinomycin, ifosfamide with the addition of etoposide

FBN

febrile neutropenia

FDG-PET

fluorodeoxyglucose positron emission tomography

FFS

failure-free survival

FH

favorable histology

FLAG-Ida

fludarabine, cytarabine, GCSF, idarubicin

FUO

fever of unknown origin

GBM

glioblastoma multiforme

G-CSF

granulocyte colony-stimulating factor

G-CSFR

granulocyte colony-stimulating factor receptor

GFR

glomerular filtration rate

GM-CSF

granulocyte macrophage colony-stimulating factor

GO

gemtuzumab ozogamicin

HAM

high-dose cytosine arabinoside and mitoxantrone

Hb

hemoglobin

HB

hepatoblastoma

HCR

hematological remission

Hct

hematocrit

HD

Hodgkin disease

HDAT

high dose cytarabine, daunomycin, thioguanine

HDCT

high-dose chemotherapy

HD L-ASP

high-dose L-asparaginase

HDMP

high-dose methylprednisolone

HDMTX

high-dose methotrexate

HIDAC

high-dose cytarabine and L-asparaginase

HL

Hodgkin lymphoma

HLA

human leukocyte antigen

HPLC

high-performance liquid chromatography

HR

hazard ratio, high-risk

HSCT

hematopoietic stem cell transplantation

HVOD

hepatic veno-occlusive disease

HYFRT

hyperfractionated radiotherapy

HYSN

hydrocortisone

IA

intra-arterial

IBI

invasive bacterial infection

IC

intensive chemotherapy

ID

intermediate dose

IDA

idarubicin

IE

ifosfamide and etoposide

IF

involved field

IFI

invasive fungal infection

IGF-1R

insulin-like growth factor-1 receptor

IL

interleukin

IM

intramuscular; interim maintenance

INRC

International Neuroblastoma Response Criteria

INSS

International Neuroblastoma Staging System

IR

incomplete response; intermediate risk

IRSG

Intergroup Rhabdomyosarcoma Study Group

IT

intrathecal

ITP

idiopathic thrombocytopenic purpura

IV

intravenous

IVA

ifosfamide, vincristine, actinomycin D

L-ASP

L-asparaginase

LCL

large cell lymphoma

LD

low-dose

LDH

lactate dehydrogenase

LFS

leukemia-free survival

LMB

Lymphome Maligne B

LR

low risk

LRFN

low-risk febrile neutropenia

LV

left ventricular

LVEF

left ventricular ejection fraction

MAP

methotrexate, doxorubicin, cisplatin

MDD

minimal detectable disease

MDS

myelodysplastic syndrome

M-EDTA

minocycline and edetic acid

MFS

metastasis-free survival

MGCT

malignant germ cell tumor

MLBCL

mediastinal large B-cell lymphoma

MOPP

mustine, vincristine, procarbazine, prednisolone

MRC

Medical Research Council

MRD

minimal residual disease

MRI

magnetic resonance imaging

MRSA

methicillin-resistant Staph. aureus

MSK

musculoskeletal; Memorial Sloan-Kettering

MT

maintenance treatment

mTOR

mammalian target of rapamycin

MTP

muramyl tripeptide

MTX

methotrexate

MTXN

mitoxantrone

MTX/VCR

methotrexate and vincristine

NBL

neuroblastoma

NCI

National Cancer Institute

NHL

non-Hodgkin lymphoma

NOS

not otherwise specified

NWTSG

National Wilms Tumor Study Group

OPP

oncovin, procarbazine, prednisone

OR

odds ratio

OS

overall survival; osteosarcoma

PBSC

peripheral blood stem cell

PBSCT

peripheral blood stem cell transplantation

PCR

polymerase chain reaction

PCV

prednisolone, CCNU, vincristine

PD

progressive disease

PDN

prednisolone

PEG

polyethylene glycol

PEG ASP

pegylated asparaginase

PET

positron emission tomography

PFS

progression-free survival

PNET

primitive neuroectodermal tumor

PO

per os

POG

Pediatric Oncology Group

PR

partial response

PRS

postrecurrence/relapse survival

PTCL

peripheral T-cell lymphoma

PVB

cisplatin, vinblastine, bleomycin

RCC

renal cell carcinoma

RCT

randomized controlled trial

RECIST

Response Evaluation Criteria for Solid Tumors

RER

rapid early response

RFS

relapse-free survival

rhEPO

recombinant human EPO

RHR

relative hazard rate

RI

remission induction

RMS

rhabdomyosarcoma

RQ-PCR

real-time quantitative polymerase chain reaction

RR

relative risk; risk ratio

RT

radiotherapy/radiation therapy

RTOG

Radiation Therapy Oncology Group

SD

standard deviation

SDI

single delayed intensification

SE

standard error

SER

slow early response

SFOP

French Society for Paediatric Oncology

SIOP

International Society of Paediatric Oncology

SIR

standardized incidence ratio

SMN

second malignant neoplasm

SR

standard risk

STD

fractionated actinomycin D

STS

soft tissue sarcomas

T-ALL

T-cell acute lymphoblastic leukemia

TCR

T-cell receptor

TG

thioguanine

TIT

triple intrathecal

TLP

traumatic lumbar puncture

TNHL

T-cell non-Hodgkin lymphoma

TPO

thrombopoietin

TRM

treatment-related mortality

UDS

undifferentiated sarcoma

UH

unfavorable histology

VA

vincristine and actinomycin

VAC

vincristine, actinomycin D, cyclophosphamide

VACA

vincristine, doxorubicin, dactinomycin, cyclophosphamide

VAI

vincristine, dactinomycin, ifosfamide

VAIA

vincristine, doxorubicin, dactinomycin, ifosfamide

VCR

vincristine

VDC

vincristine, doxorubicin, cyclophosphamide

VEGF

vascular endothelial growth factor

VGPR

very good partial response

VIDE

vincristine, ifosfamide, doxorubicin, etoposide

VIE

vincristine, ifosfamide, etoposide

VM

vincristine and melphalan

VTC

vincristine, topetecan, cyclophosphamide

WBC

white blood cell

WHO

World Health Organization

WT

Wilms tumor

About the companion website

Website: Evidence-Based Medicine Series

The Evidence-Based Medicine Series has a website at:

www.evidencebasedseries.com

Where you can find:

Links to companion websites with additional resources and updates for books in the seriesDetails of all new and forthcoming titlesLinks to more Evidence-Based products: including the Cochrane Library, Essential Evidence Plus, and EBM Guidelines.

How to access the companion sites with additional resources and updates:

Go to the Evidence-Based Series site:www.evidencebasedseries.comSelect your book from the list of titles shown on the siteIf your book has a website with supplementary material, it will show an icon next to the titleClick on the icon to access the website

PART 1

Solid tumors

CHAPTER 1

Rhabdomyosarcoma

Katherine K. Matthay

UCSF School of Medicine, San Francisco, CA, USA

Commentary by Meriel Jenney

Philosophy of treatment of rhabdomyosarcoma

Soft tissue sarcomas (STS) account for about 8% of all childhood malignancies. Rhabdomyosarcoma (RMS) is the single most common diagnosis (accounting for approximately 60% of all STS). It is, consequently, the tumor which is best defined, although there are ­important differences in behavior between RMS and some of the non-RMS STS (e.g. metastatic potential, chemosensitivity).

Historically, there have been important differences in the philosophy of treatment of RMS between the major international collaborative groups. Although there is now good communication, and a convergence toward standard criteria for staging and pathological classification, the experience of reviewing the ­literature can be confusing, particularly with respect to the ­previous lack of use of standard terminology for ­staging and treatment stratification.

One of the most important philosophical differences between the International Society of Paediatric Oncology (SIOP MMT) studies and those of the Intergroup Rhabdomyosarcoma Study Group (IRSG) (and, to some extent, those of the German [CWS] and Italian [ICG] Cooperative Groups) relates to the method and timing of local treatment. In particular, to the place of radiotherapy (RT) in guaranteeing local control for patients who appear to achieve ­complete remission (CR) with chemotherapy, with or without “significant” surgery. The SIOP strategy ­recognizes that some patients can be cured without the use of radiotherapy or so-called “significant’ ­surgery,” i.e. surgery resulting in considerable long-term morbidity. However, with this approach local relapse rates are generally higher in the SIOP studies than those ­experienced elsewhere, although the SIOP experience has also made it clear that a significant number of patients who relapse may be cured with alternative treatment (the so-called “salvage gap” between event-free and overall survival). In the ­context of such differences, overall survival rather than disease-free or progression-free survival becomes the most important criterion for comparing studies and measuring outcome

Treatment: the general approach

Rhabdomyosarcoma can occur almost anywhere in the body (although a number of well-recognized sites have been defined, e.g. bladder, prostate, ­parameningeal, limb, genitourinary, and head and neck). This leads to a complexity in its treatment and although the majority of clinical trials have explored chemotherapeutic options for the treatment of RMS, the impact of the site of disease should not be ­overlooked. Experience in all studies has confirmed that a surgical-­pathological classification, which groups patients according to the extent of residual tumor after the initial surgical ­procedure, predicts outcome. The great majority of patients (approximately 75%) will have macroscopic residual disease (IRS clinical group III) at the primary site at the start of chemotherapy (this is equivalent to pT3b in the SIOP postsurgical staging system). The additional adverse prognostic influence of tumor site, size (­longest dimension >5 cm), histological subtype (alveolar versus embryonal) and patient age (>10 years) adds to the complexities of treatment ­stratification. All current clinical trials utilize some combination of the best-known prognostic factors to stratify treatment intensity for patients with good or poor predicted ­outcomes and the impetus for this approach comes as much from wishing to avoid ­overtreatment of patients with a good prospect for cure as improving cure rates for patients with less favorable disease.

The importance of multiagent chemotherapy, as part of co-ordinated multimodality treatment, has been clearly demonstrated for RMS. Cure rates have improved from approximately 25% in the early 1970s, when combination chemotherapy was first ­implemented, to the current overall 5-year survival rates of more than 70% that are generally achieved. Nevertheless, it is interesting to see how relatively little the results of randomized controlled trials have ­actually contributed to decision making in the ­selection of chemotherapy and to the development of the design of the sequential studies which have shown this ­improvement in survival over those years.

Lessons from studies of rhabdomyosarcoma

The IRSG was formed in 1972 as a collaboration between the two former pediatric oncology groups in North America (Children’s Cancer Group and Pediatric Oncology Group [POG]) with the intention of investigating the biology and treatment of RMS (and undifferentiated sarcoma) in the first two ­decades of life. This group, whose work and publications have been pre-eminent in the field, now forms the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG). Results of treatment have improved significantly over time. The percentage of patients alive at 5 years has increased from 55% on the IRS-I protocol [1] to over 70% on the IRS-III and IRS-IV protocols [2,3].

Combinations of vincristine, actinomycin D, and cyclophosphamide (VAC) have been the mainstay of chemotherapy in all IRS studies. Actinomycin-D was originally given in a fractionated schedule but ­subsequent experience, including a randomized study from Italy [4], showed no advantage in terms of outcome and has suggested that fractionation may increase toxicity; single-dose scheduling is now standard across all studies. There have never been any results in the IRSG studies that challenge the use of these drugs as first-line therapy and the results of all randomized studies which compare other drugs with, or against, VA or VAC have failed to show significant advantage.

One of the most significant differences between the IRSG and European studies has been in the choice of alkylating agent that provides the backbone of ­first-line chemotherapy. Ifosfamide was introduced into clinical practice earlier in Europe than in the United States and phase II data are available which support its ­efficacy in RMS. IRS-IV [2, 3] attempted to answer the question of comparative efficacy by ­randomizing VAC (using an intensified cyclophosphamide dose of 2.2 g/m2) against vincristine/­dactinomycin/ifosfamide (VAI), which incorporated ifosfamide at a dose of 9 g/m2. A third arm in this ­randomization included ifosfamide in combination with etoposide (VIE; vincristine, ifosfamide, etoposide). No difference was identified between the higher-dose VAC and the ifosfamide-­containing schedules, and VAC remains the ­combination of choice for future IRSG (now COG) studies. The rationale for this is explained by the lower dose of cyclophosphamide and its shorter duration of administration, together with concern about the nephrotoxicity of ifosfamide. Nevertheless, the European Paediatric Soft Tissue Sarcoma Group (EpSSG) has chosen to retain ­ifosfamide as its standard combination as the experience of significant renal toxicity at cumulative ifosfamide doses less than 60 g/m2 is now very small and there are preliminary data suggesting that the gonadal toxicity of ifosfamide may be significantly less than that of cyclophosphamide [5].

Vincristine, actinomycin D, and cyclophosphamide remains the chemotherapy backbone for IRS studies, as there has been little evidence of benefit from other agents. IRS-III included cisplatin and etoposide in a three-way randomization between VAC, VAC with doxorubicin and cisplatin, and VAC with doxorubicin, cisplatin, and etoposide. No advantage was seen in selected group III and all group IV patients and there were concerns about additive toxicity. IRS-IV (and an earlier IRS-IV pilot) explored the value of melphalan in patients with metastatic RMS or undifferentiated sarcoma. Patients were randomized to receive three courses of vincristine and melphalan (VM) or four of ifosfamide and etoposide (IE) [6]. There was no ­significant difference in initial complete and partial remission rates. However, patients receiving VM had a lower 3-year event-free and overall survival. Patients receiving this combination had greater hematological toxicity and, therefore, a lower tolerance of subsequent therapy. In the latest published randomized study by the COG (D9803) [7] in patients with intermediate-risk RMS, VAC was compared to a regimen of VAC alternating with vincristine, topotecan, and ­cyclophosphamide. Again, no benefit was seen with use of these agents.

Alternative agents of particular interest include doxorubicin (Adriamycin), which has been evaluated in a number of IRSG studies. A total of 1431 patients with group III and IV disease were randomized to receive or not receive doxorubicin in addition to VAC during studies in IRS-I to IRS-III. The results did not indicate any significant advantage for those who received doxorubicin. Furthermore, also in IRS-III, patients with group II (microscopic residual) tumors were randomized between vincristine and actinomycin (VA) alone and VA with ­doxorubicin without any significant difference in ­survival. Recent European studies (MMT 95 and CWS-ICG 96) both included randomizations between their ifosfamide-based standard chemotherapy options and an intensified six-drug combination, which also included epirubicin (with carboplatin and etoposide). In the MMT 95 study [8], 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma, undifferentiated sarcoma, and soft ­tissue primitive neuroectodermal tumor were randomized to receive IVA (ifosfamide, vincristine, actinomycin D) or a six-drug combination (IVA + carboplatin, epirubicin, etoposide) both delivered over 27 weeks. Overall survival for all patients was 81% (95% ­confidence interval [CI], 77–84%) at 3 years but there was no significant difference in outcome in either overall or event-free survival between the two arms. Toxicity was ­significantly greater (infection, ­myelosuppression, mucositis) in patients in the ­six-drug arm. However, in this and the previous ­studies, the dose intensity of the anthracyclines used was low which may have influenced the evaluation.

So doxorubicin remains a drug of interest in soft ­tissue sarcomas. A SIOP “window” study in ­chemotherapy-naïve patients with metastatic RMS has ­provided good new phase II data for the efficacy of doxorubicin, with response rates greater than 65% [9]. This has justified further evaluation of the role of ­doxorubicin in the treatment of RMS and this is now under investigation in a randomized study being undertaken by the EpSSG. A more intensive scheduling of doxorubicin is being tested within this study.

Other agents that have shown activity in RMS include irinotecan (CPT11), which in combination with vincristine in a recent COG window study had excellent PR and CR rates [10]. There is also evidence of benefit in the phase I setting [11]. The scheduling of this agent in the phase II setting [12] has been evaluated in patients with RMS, undifferentiated ­sarcoma or ectomesenchymoma at first relapse or with disease progression. Although preclinical models ­suggested that a prolonged administration schedule of irinotecan would be more effective than a short (more convenient) schedule, this study demonstrated equivalent response rates (26% for prolonged schedule ­versus 36% for short) in patients receiving the two schedules. The current COG IRS-V study has now included this combination (using the short schedule) in the latest randomized study.

Vinorelbine is well tolerated and has been ­evaluated in combination with daily oral cyclophosphamide in previously heavily treated patients with relapsed RMS with encouraging results [13,14]. This combination is now under investigation in the current EpSSG study in which patients who achieve CR with ­conventional chemotherapy and local treatment are ­randomized to stop therapy or to continue to receive a further 6 months of “maintenance” therapy with these two agents.

Radiotherapy has been a standard component of therapy for the majority of patients in the IRSG studies from the outset. Randomized studies within IRS-I to IRS-III have established that RT is unnecessary for group I (completely resected) patients with embryonal histology. Analyses from the same studies suggest that RT does offer an improved failure-free survival (FFS) in patients with completely resected alveolar RMS or with undifferentiated sarcoma. Studies from the European groups have attempted to relate the use of RT to response to initial chemotherapy. The most ­radical approach is being used by the SIOP group which has tried to withhold RT in patients with group III (pT3b) disease if CR is achieved with initial ­chemotherapy ± conservative second surgery. In the MMT 89 study, which included 503 patients, the ­systematic use of RT was avoided in patients who achieved complete local tumor control with ­chemotherapy with or without surgery, Five-year ­overall survival (OS) and event-free survival (EFS) rates were 71% and 57%, respectively. The differences between EFS and OS reflected local treatment strategy and successful retreatment for some patients after relapse (the salvage gap). The authors concluded that selective avoidance of local therapy is justified in some patients, though further work is required to identify prospectively those for whom this is most applicable [15].

So this approach is warranted for some patients, for example, those with tumors of the orbit, where outcomes from different international groups have previously been formally compared at a joint ­international workshop (there were no significant ­differences in overall survival between international groups using different strategies for radiotherapy, despite differences in event-free survival) [16]. However, the role of radiotherapy is clearly important for other subgroups of patients (for example, those with parameningeal, limb, and/ or alveolar disease) and there is a need to try to define risk groups as accurately as possible at the outset to avoid ­overtreatment, and also to reduce the risk of relapse and the need for salvage therapy.

Doses of RT have, somewhat pragmatically, been tailored to age, with reduced doses in younger children, although there is no defined threshold below which late effects can be avoided and yet tumor ­control is still achieved. The place for hyperfractionated RT was explored in IRS-IV when randomized against conventional fractionation [17]. Although there was a higher incidence of severe skin reaction and nausea and vomiting in patients receiving hyperfractionated RT, it was generally well tolerated. However, there was no advantage in failure-free survival, and conventional RT continues to be used as standard therapy.

Lessons from studies of nonrhabdomyosarcoma soft tissue sarcomas

Although this chapter refers to two studies that include patients with non-RMS STS [18, 19], the former is the only published study which was specifically designed to answer a randomized question about the value of chemotherapy in this difficult and heterogeneous group of patients. Unfortunately, the power of this study was limited and further work needs to be ­undertaken to better understand optimal therapy. Perhaps the most important immediate question is to ascertain whether the treatment of children with non-RMS STS, particularly with the diagnoses more ­frequently seen in adults, should be assessed any ­differently than for adults with the same condition. If not, combined ­studies, particularly of new agents, could be productive.

An important recent development in Europe has been the initiation of a new EpSSG study specifically for children with non-RMS STS and this will facilitate the systematic collection of data from the consistent treatment of children with these rare tumors. There is also now regular communication across the Atlantic with respect to the classification and treatment of ­non-RMS STS. Separate approaches are offered for synovial sarcoma for “adult” type non-RMS STS and for unique pediatric histiotypes, and links with adult trials will also be important. None of these studies yet includes a randomized element and the numbers of patients in some of these rare diagnostic groups, even when collected at European level, still make this a logistical and statistical challenge.

Conclusion

Although considerable progress has been made in improving overall survival in RMS, progress has been incremental and intuitive, based on careful treatment planning, the co-ordination of chemotherapy with surgery and RT, and better prognostic treatment ­stratification. Relatively little has been learned about improving treatment from randomized studies but previous conclusions about the role of doxorubicin are being revisited and further new agents (irinotecan, vinorelbine) are under evaluation. The challenge for the future requires the development of a greater ability to selectively reduce treatment for some groups of patients with a high chance of cure and to identify ­better forms of therapy for those with a very poor prognosis. Patients with metastatic disease, for ­example, continue to have a very poor survival rate. Wider international collaboration is the key to ­providing a patient base that will allow timely and valid randomized studies.

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