Evidence-Based Pediatric Oncology

Ross Pinkerton, A. G. Shankar, Katherine Matthay, Ross Pinkerton, A. G. Shankar, Katherine Matthay

• Publisher: Wiley-Blackwell
• Year: 2013
• Print ISBN: 9780470659649
• eBook ISBN: 9781118625170
• Edition: 3
• Topic: Medicine
• Subtopic: Oncology

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.

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, althoug...

Table of contents

• Cover
• Title page
• Copyright page
• List of contributors
• Preface
• List of abbreviations
• About the companion website
• PART 1: Solid tumors
• PART 2: Leukemia
• PART 3: Supportive care in pediatric oncology
• Index