ORIGINAL ARTICLE

Preradiation Chemotherapy for Adult High-risk

Medulloblastoma
A Trial of the ECOG-ACRIN Cancer Research Group (E4397)
Paul L. Moots, MD,* Anne O’Neill, MS,w Harold Londer, MD,z
Minesh Mehta, MD,y Deborah T. Blumenthal, MD,8 Geoffrey R. Barger, MD,z
Margaret L. Grunnet, MD,# Stuart Grossman, MD,** Mark R. Gilbert, MD,ww
and David Schiff, MDzz

43.8 months. Five-year PFS was 27%. Five-year OS was 55%. Non-
Objectives: To assess the long-term outcomes and objective response metastatic (M0) and metastatic (M +) patients had similar outcomes.
(OR) to preradiation chemotherapy and radiation in adult high-risk
medulloblastoma. Conclusions: The OR to this preradiation chemotherapy regimen is
lower than anticipated from the adult and pediatric literature raising a
Materials and Methods: In this prospective phase II trial, adults with question about comparative efficacy of chemotherapy in different age
high-risk medulloblastoma were treated with 3 cycles of preradiation groups. The OS achieved is similar to retrospective adult series, but
cisplatin, etoposide, cyclophosphamide, and vincristine followed by worse than pediatric outcomes. Although this regimen can be admin-
craniospinal radiation (CSI). OR, progression-free survival (PFS), istered without compromising delivery of CSI, our results do not
overall survival (OS), and toxicities were assessed. provide support for the use of this neoadjuvant chemotherapy for adult
medulloblastoma.
Results: Eleven patients were enrolled over a 6-year period. Six (55%)
had subarachnoid metastases. Two (18%) had an OR to preradiation Key Words: adult medulloblastoma, preradiation chemotherapy,
chemotherapy. Two (18%) progressed while on chemotherapy. Com- phase II trial
pletion of CSI was not compromised. The OR rate after chemotherapy
and radiation was 45% (5/11). Nonevaluable patients at both time- (Am J Clin Oncol 2016;00:000–000)
points weakened the response data conclusions. Median PFS was

From the *Vanderbilt University and TVHS, Nashville, TN; wDana Farber
Cancer Institute, Boston, MA; zHumphrey Cancer Center, Robbins-
dale, MN; yDepartment of Human Oncology, University of Wisconsin,
M edulloblastoma in adults is rare, with an incidence of 0.5
per million per year.1 As a result, treatment strategies for
adults with medulloblastoma are largely inferred from pediatric
Madison, WI; 8Division of Oncology, University of Utah, Salt Lake results. Prospective pediatric trials have established that gross
City, UT; zDepartment of Neurology, Wayne State University, Detroit,
MI; #University of Connecticut Health Center, Farmington, CT;
residual disease at the primary tumor site after surgery and
**Johns Hopkins University Medical Center, Baltimore, MD; wwM.D. evidence of dissemination are independent negative prognostic
Anderson Cancer Center, Houston, TX; and zzUniversity of Virginia factors. Disease staging for adults using similar criteria seems to
Medical Center, Charlottesville, VA. have prognostic significance, distinguishing between standard-
Present address: Minesh Mehta, MD, University of Maryland, Baltimore,
MD.
risk and high-risk groups, although not all reports confirm this
Present address: Deborah T. Blumenthal, MD, Tel-Aviv Sourasky Medical observation, particularly with long-term follow-up.2–5 The
Center, Tel-Aviv, Israel. addition of adjuvant chemotherapy for children with high-risk
Present address: Mark R. Gilbert, MD, National Institutes of Health, medulloblastoma improves progression-free survival (PFS) and
Bethesda, MD.
This study was coordinated by the ECOG-ACRIN Cancer Research Group
overall survival (OS).6–8 This strategy has frequently been
(Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co- applied in adult patients, but without prospective controlled trial
Chairs) and supported in part by Public Health Service Grants evidence.
CA180820, CA180794, CA21115, CA23318, CA66636, CA180847, In recent years the molecular classification of medullo-
CA49957, CA189863, CA35267, CA180799, CA21076, CA180888,
CA32102, CA180818, CA58861, CA180835, CA14028, CA180802,
blastoma has advanced greatly and provided new insights into
CA16116, CA180844, CA39229, CA180858, and from the National biological similarities and differences between pediatric and
Cancer Institute, National Institutes of Health and the Department of adult medulloblastoma.9–13 The issue of therapeutic inferences
Health and Human Services. Its contents are solely the responsibility of for adult medulloblastoma from pediatric results is becoming
the authors and do not necessarily represent the official views of the
National Cancer Institute.
increasingly complex as the role of molecular subgroups in risk
M.M. has served in the past as a consultant for Genentech, Novartis, with stratification increases.12,13 Since the ability to perform large-
stock options in Pharmacyclics, and is on the Board of Directors of scale randomized clinical trials for adult medulloblastoma is
Pharmacyclics. The remaining authors declare no conflicts of interest. hampered by small patient numbers, execution of smaller trials
Reprints: Paul L. Moots, MD, Vanderbilt University and TVHS, Nashville,
TN 37232. E-mail: [email protected].
with fewer patients, generally using historical controls and
Supplemental Digital Content is available for this article. Direct URL often including comparison with pediatric medulloblastoma
citations appear in the printed text and are provided in the HTML and patients represents a possible “screening” strategy for various
PDF versions of this article on the journal’s Website, www.amjclinical regimens.
oncology.com.
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E4397 was a phase II trial of preradiation chemotherapy
ISSN: 0277-3732/16/000-000 for high-risk medulloblastoma in adults based closely on a
DOI: 10.1097/COC.0000000000000326 pediatric regimen which included cisplatin (CDDP), etoposide

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 Moots et al American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2016

(Etop), cyclophosphamide (Cyclo), and vincristine (Vcr) and 36 Gy as the craniospinal dose with boosts to sites of
monthly for 3 cycles, followed by craniospinal radiation obvious metastatic disease. A daily fraction size of 1.8 Gy was
(CSI).14–16 The primary aim of E4397 was to evaluate the used for all sites.
objective response (OR) rate after preradiation chemotherapy
and after completion of radiation. The secondary objectives
were to evaluate PFS, OS, and toxicities. This study was Assessment of Response and Toxicity
undertaken by the Eastern Cooperative Oncology Group For assessment of response to treatment, the brain MRI
(ECOG-ACRIN) and Southwestern Oncology Group (SWOG). was repeated on day 28 of cycles 1 and 2 of chemotherapy,
and the spine MRI was repeated if initially positive. Brain
and total spine MRI were repeated before the start of radia-
MATERIALS AND METHODS tion. Brain MRI was performed following the completion of
Patients above 18 years of age with histologically veri- radiation, then every 3 months for 2 years from study entry,
fied, newly diagnosed medulloblastoma with high-risk char- then every 6 months for 5 years from study entry, and then
acteristics, defined as either >1.0 cm2 residual tumor at the annually. Total spine MRI was performed on the same
primary site after surgery, or evidence of subarachnoid dis- schedule if it had ever been positive, or on a yearly basis. CSF
semination (M +) were eligible for this study and are included cytology was obtained before the first cycle of chemotherapy,
in this report. Patients with supratentorial PNET and ependy- just before radiation, and at completion of radiation. Sub-
moma with subarachnoid dissemination were also eligible and sequent CSF testing was performed if new symptoms or
are summarized in the Appendix (see Supplemental Material, radiographic changes occurred.
Supplemental Digital Content 1, http://links.lww.com/AJCO/ Assessments of the patient’s overall health, history and
A146). physical examination, neurological examination, and per-
Initial staging included brain magnetic resonance imaging formance status were performed at baseline, day 28 of che-
(MRI) obtained within 48 hours postoperatively to assess motherapy cycles 1 and 2, before radiation therapy, at com-
residual disease. MRI of the entire spine and cerebrospinal fluid pletion of radiation therapy, every 3 months until 2 years from
(CSF) cytology were obtained following surgery before enroll- study entry, every 6 months until 5 years from study entry, and
ment. All MRI scans were performed without and with gadoli- then annually. Hematologic evaluations were obtained at
nium contrast. Imaging results were reported based on local baseline, weekly during chemotherapy, before radiation ther-
interpretation. apy, at completion of radiation therapy, every 3 months until 1
Patients were required to have a stable corticosteroid year from study entry, then annually. Audiograms were per-
dosage, no midline shift >1 cm, and no intracranial pressure formed before treatment and repeated only if grade 2 or greater
elevation. ECOG performance status could be 0 to 2. Adequate tinnitus or hearing loss were reported.
hematologic parameters (WBC > 4000/mm3, platelets > 125,000/ Complete response (CR) was defined as disappearance of
mm3, Hgb > 10 gm), no clinically significant serum chemistry all disease demonstrated by MRI and negative CSF cytology.
abnormalities, liver enzymes < 2 normal, creatinine clearance Persistence of small areas of T2 hyperintensity without con-
>70 mL/min, and no history of pulmonary disease or DlCO trast enhancement at the primary tumor site, persistent
>60% predicted were required. No prior treatment with radiation meningeal enhancement at the operative site, or smooth diffuse
or chemotherapy was allowed. Enrollment was to be between 10 dural enhancement were not scored as residual disease.
and 21 days after surgery. Institutional IRB approval and Patients must have been off steroids, and response must have
informed consent were required. been sustained for >4 weeks. Partial response (PR) was a
The chemotherapy plan utilized three 28-day cycles decrease of at least 50% in the sum of the cross-section
including: (1) CDDP 70 mg/m2 on day 1; (2) Etop 70 mg/m2 on products of all measurable lesions. Steroid dose must have
days 1, 2, and 3; (3) Cyclo 700 mg/m2 on days 2 and 3; and (4) been stable or decreasing. Stable disease was no change, an
Vcr 1.5 mg/m2 (maximum, 2.0 mg) on days 1 and 14 of each increase of <25%, or a decrease of <50% in all measurable
cycle. Mesna, 70 mg/m2 bolus followed by 700 mg/m2 by lesions, persistently negative cytology, and no new areas of
continuous infusion over 24 hours following Cyclo was given. meningeal enhancement. Progressive disease (PD) was an
All patients received granulocyte-colony stimulating factor, increase of >25% in any measurable lesion, the development of
300 mcg per day for 10 days following each cycle (Table 1). new lesions, either parenchymal or meningeal. The demon-
CSI began 4 weeks following completion of chemo- stration of persistently positive or newly positive CSF cytology
therapy. The radiation plan called for 54 Gy to the primary site following chemotherapy was considered PD.

TABLE 1. E4397 Chemotherapy Regimen

Day
Treatment 1 2 3 4 13 15 28
Cisplatin (70 mg/m2) X
VP-16 (70 mg/m2/d) X X X
Cyclophosphamide (700 mg/m2/d) X X
Vincristine (1.5 mg/m2, max 2.0 mg) X X
CGSF (for weight <85 kg: 300 mcg/d  10d, for weight Z85 kg: 4 to 13
480 mcg/d 10d)
Mesna (70 mg/m2 bolus IV followed by 700 mg/m2/d infusion) X X
The treatment plan used in E4397 included 3 cycles of preradiation chemotherapy delivered at 4-week intervals. This was followed by radiation to a dose of 54 Gy to
the primary tumor site and 36 Gy to the craniospinal axis, delivered in daily fractions of 1.8 Gy. Sites of obvious metastatic disease received an additional radiation boost.

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 American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2016 Chemotherapy for Adult High-risk Medulloblastoma

New focal meningeal or subependymal enhancement

demonstrated by MR scanning was considered evidence of PD TABLE 2. Patient Characteristics
even though those lesions were not often measurable. Diffuse N = 11 (n [%])
dural enhancement in the absence of positive cytology or Sex
progressive clinical symptoms was not considered PD. Female 6 (55)
Toxicity summaries include all medulloblastoma patients Male 5 (45)
who began protocol treatment. CTC version 2.0 was used. Race
White 10 (91)
Statistical Methods Other 1 (9)
The primary endpoint was to estimate the OR (CR + PR). Age
Secondary endpoints included 5-year PFS and OS. Planned Minimum 21
accrual was 33 patients. A stopping rule would have halted 25th percentile 23
Median 35
accrual if Z7 of the first 10 patients were unable to complete 2 75th percentile 39
cycles of chemotherapy. PFS was defined as time from date of Maximum 39
registration to evidence of PD or death without PD. Patients ECOG performance status
without evidence of progression were censored at the date last (0) Fully active 5 (45)
known to be free of progression. OS was defined as time from (1) Ambulatory 3 (27)
registration to death from any cause. Patients alive at time of (2) Self care, but not work 3 (27)
current analysis were censored at the date last known to be Surgery
alive. The Kaplan-Meier method was used to estimate PFS and Biopsy only 2 (18)
survival distributions. Confidence intervals (CIs) for median Resection 9 (82)
Metastases
PFS and survival were calculated using the method of M0 5 (45)
Brookmeyer and Crowley.17,18 M+ 6 (55)

RESULTS
Patient Accrual grade 4 renal toxicity. Two patients had mild hearing loss. One
E4397 opened in July 1998 and closed in September death occurred during treatment, but was not considered
2004. Eleven medulloblastoma patients were enrolled for an treatment related. This was suspected to be from a pulmonary
accrual rate of 1.8 patients per year. The diagnosis of medul- embolus.
loblastoma was confirmed by central pathology review in 8 of Response Assessment
11 cases. The median age was 35 years with a range from 21 to
The OR at conclusion of chemotherapy for the 11
39 years (Table 2). Six of 11 patients (55%) were M + . The
medulloblastoma patients was 18% (2/11) (95% CI, 2.2%-
study was open at many ECOG and SWOG institutions;
51.7%), with 1 CR and 1 PR. In 3 patients disease stabilized.
however, only 10 institutions enrolled patients, and only 3
Progression before starting radiation was observed in 18% (2/
enrolled >1 patient. The study was closed primarily due to
11). Four patients were not evaluable for response at the
slow accrual.
conclusion of chemotherapy including 1 on steroids, 1 who
Treatment Parameters refused a spinal tap, 1 whose follow-up was by computed
Eighty-two percent (9/11) of the medulloblastoma tomography (CT), and 1 with incomplete information.
patients had a major resection. Two patients had biopsy only. OR at completion of chemotherapy and radiation was
Ninety-one percent (10/11) of the medulloblastoma 45% (5/11) (95% CI, 16.7%-76.2%). Twenty-seven percent (3/
patients completed chemotherapy. One patient progressed after 11) achieved a CR, and 18% (2/11) achieved a PR. In 18% (2/
2 cycles, and 1 progressed after the third cycle but before 11) disease stabilized. PD was seen in 9% (1/11). Three
radiation. patients were not evaluable for response at the completion of
Eighty-two percent (9/11) of the medulloblastoma all therapy including 1 patient who refused a spinal tap to
patients completed CSI. One refused treatment beyond the 3 confirm CR, 1 whose follow-up was by CT, and 1 with
cycles of chemotherapy and 1 died just before RT from an incomplete information.
acute cardiopulmonary event. Median primary tumor dose was Outcome
54 Gy (range, 54.0 to 54.6 Gy). Median craniospinal dose was
At the time of analysis the median follow-up was 63
36 Gy (range, 36 to 45 Gy). Median interval from surgery to
months. Median PFS was 43.8 months (95% CI, 2.0-73 + [upper
the start of radiation was 17.7 weeks (range, 14.8 to 21.4 wk).
limit not reached as last patient censored at 71.3 mo]). Five of 11
The median duration of RT was 6.5 weeks (range, 5.0 to
patients have died. Median survival has not been reached. Five-
7.0 wk).
year OS was 55% and PFS was 27% (Fig. 1). Median PFS was
Toxicities 41.2 months for the 5 M0 patients, and 59.3 months for the 6
The pattern of toxicities was as anticipated from prior M + patients. Five-year OS was 60% and PFS 20% for M0
experience with this chemotherapy regimen and CSI15,16,19 patients versus 50% OS and 30% PFS for M + patients.
(Table 3). Among 11 medulloblastoma patients 6 experienced
grade 3 toxicities and 4 experienced grade 4 toxicities. These DISCUSSION
were predominantly hematologic toxicities, fatigue, nausea, The SEER database of all medulloblastoma patients
vomiting, and anorexia. Two patients experienced fever or above 18 years of age shows 5- and 10-year survival rates of
infection while neutropenic. Two patients experienced grade 4 64% and 50%, respectively, with a 10.6-year median sur-
radiation dermatitis. Minor electrolyte alterations were com- vival.20,21 In series reporting long-term outcome for adults
mon but rarely significant. One patient experienced transient with high-risk disease the 5-year PFS ranges from 38% to 61%

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 Moots et al American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2016

platinum-based regimens assessed retrospectively, many of

TABLE 3. Toxicity Incidence for 11 Medulloblastoma Patients: whom were treated at recurrence. The sparse response data
CTC Version 2.0 was Used for Toxicity Grading
regarding upfront chemotherapy for high-risk medulloblastoma
Grade 1,2 (n) 3 (n) 4 (n) 5 (n) in the adult literature, totaling 12 patients, suggest an OR of
Toxicity >50%.24,25
Hemoglobin 9 1 In pediatric phase II and III trials utilizing preradiation
Leukocytes 6 4 1 chemotherapy, response rates range from 29% to 74%. Pro-
Neutrophils 3 1 4 gression before radiation is typically observed in about 20%,
Platelets 8 3 with reports ranging from 0% to 38%.8,14,15,26–33 The OR is
Transfusions: platelets 1 lower and progression before radiation more likely in M +
Transfusions: pRBCs 1 children.27–29 Three pediatric randomized trials for high-risk
Febrile neutropenia 1
Infection 1 2
medulloblastoma patients using preradiation CDDP/Cyclo-
Hypernatremia 2 containing regimens, followed by CSI and maintenance che-
Hyponatremia 3 1 motherapy, 2 of which were reported while E4397 was
Hypokalemia 2 1 underway, did not demonstrate improved OS.8,29,30,32 The best
Hyperglycemia 10 results reported for pediatric high-risk medulloblastoma
Hypoglycemia 1 patients were achieved by Packer using CSI with concurrent
Hypercalcemia 1 Vcr and postradiation CCNU, CDDP, and Vcr. The 5-year PFS
Hypocalcemia 5 was 85%, with M0 patients faring better than M + patients.34
Hypermagnesemia 1 This regimen has not been as successful or as well tolerated in
Hypomagenesemia 5
Creatinine 1
adults.23,24 Jakacki et al35 observed a 80% 5-year OS and 66%
Alkaline phosphatase 5 PFS for M + children treated with carboplatin and vincristine
SGOT 3 concurrent with Cr-Sp RT, followed by maintenance
Billirubin 1 chemotherapy.
Fatigue 7 3 The only other prospective adult medulloblastoma trial was
Weight loss 5 reported by Brandes and colleagues and included a total of 36
Weight gain 3 patients, of whom 26 had high-risk disease. They observed a 5-
Anorexia 3 3 year OS of 73% and a 5-year PFS of 69% for high-risk
Dehydration 1 1 patients.4,36 That cohort had a slightly shorter interval from
Dsyphagia 3
surgery to radiation than in E4397 (13.9 vs. 17.7 wk), and risk
Mucositis/stomatitis 4 1
Nausea 7 2 categorization was not identical to E4397, using residual disease
Vomiting 3 2 1 of >1.5 cm2 or M + staging. The percentage of M + patients in
Confusion 1 the Brandes trial was 60% and in E4397 was 55%. Thus the
Dizziness 4 difference in results does not relate to the percentage of M +
Syncope 1 patients. Of note, after a median follow-up of 7.6 years, M status
Anxiety/agitation 2 1 and residual disease after surgery did not have a significant
Personality change 1 effect on PFS or OS, and the difference in outcome between
Memory loss 2 low-risk and high-risk patients was no longer significant. This
Tremor 1
was attributed to late recurrences in the low-risk group.4,36
Blurred/double vision 4
Hearing loss 2 E4397 confirms the feasibility of delivering moderately
Neuropathy 5 1 intensive multiagent chemotherapy before CSI without
Bone pain 1 altering the planned radiation schedule. The median duration
Headache 5 of radiation was 6.5 weeks. A more protracted radiation
Myalgia 3 course has been associated with worse outcome.37 Delays in
Arthralgia 2 starting RT have been associated with poorer outcome in
Irregular menses 3 1 pediatric trials.8,28–30 In E4397 the median duration from
Radiation dermatitis/recall 2 surgery to initiation of radiation was 17.7 weeks (range, 14.8
Alopecia 10
to 21.4 wk).
Cushingoid features 2
Worst degree 1 6 4 Conclusions drawn from E4397 are limited by small
patient numbers, an inherent problem of looking at a subgroup
of patients in an already rare disease. Multi-institutional
and 5-year OS ranges from 54% to 69%.2,4,22 The 5-year PFS studies are critical for trials of rare cancers, and the coopera-
of 27% observed in E4397 is lower than that reported in the tive group setting is well-suited for this. E4397 was open at
literature. The 5-year OS of 55% in these 11 high-risk patients many ECOG-ACRIN and SWOG institutions, however, only
is similar to those reports. Our results do not suggest an 10 accrued patients and most accrued only 1 patient. The rate
advantage in long-term outcome with this preradiation che- of enrollment was 1.8 patients per year. The trial by Brandes
motherapy regimen. M + patients do worse than M0 patients in et al4 enrolled 2.16 high-risk medulloblastoma patients per
most, but not all reports.13,22–24 In E4397 there was little dif- year. At the institutional and the cooperative group level that
ference in outcome between the M0 and M + patients. accrual rate is too low to offset efforts required to maintain the
The chemotherapy response rate (OR) of 18% suggests a study. These pressures contributed to the closure of E4397.
lower chemotherapy efficacy than had been anticipated from One practical solution would be to utilize only institutions
prior adult reports. However, this conclusion is limited by the demonstrating a history of treating a set minimum number of
small number of patients, including the fact that 4 patients were patients per year who fit the eligibility criteria. Using a mul-
not evaluable for response at completion of chemotherapy. tinational intergroup format may also facilitate better accrual.
Galanis et al23 reported an 85% OR for adult patients using Small patient numbers also magnify the effect of patient

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 American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2016 Chemotherapy for Adult High-risk Medulloblastoma

FIGURE 1. A and B, Assessment of outcome in E4397 at a median follow-up of 63 months demonstrates a median progression-free
survival (PFS) of 43.8 months (95% CI, 2.0-73 + [upper limit not reached as last patient censored at 71.3 mo]), and a 5-year PFS of 27%.
Median survival has not been reached. The 5-year overall survival (OS) is 55%.

inevaluability for endpoints such as OR, and subsequent con- disease was still being assessed with mixed reports in the early
clusions are weakened as a result. However, assessing response 1990s regarding its prognostic significance. In 1997 Albright
rates using only evaluable patients inappropriately inflates the published data now considered the consensus standard, indi-
OR. Promoting better accrual and requiring central review of cating that residual disease >1.5 cm2 assessed by CT or MRI
response are two ways to improve future trials. was associated with higher risk of recurrence.8,39 Although our
Evolution of therapies also has an impact on accrual to criteria for high-risk differed slightly from that standard, the
trials for rare diseases. Maintaining studies over extended use of a smaller cutoff ( > 1.0 cm2) for postoperative residual
periods often fails to keep up with evolving trends and newer disease does not seem to have biased the results toward a more
therapies. This led to a substantial revision in the protocol favorable outcome. A recent observational report of adult
utilized by Brandes et al.36 Similarly, the publication of neg- patients with nonmetastatic medulloblastoma reported that
ative neoadjuvant pediatric medulloblastoma trials while patients with any residual tumor fared more poorly than those
E4397 was in progress was another influential factor in the without.40 This issue continues to generate discussion as
decision to close E4397.8,29 residual tumor was not a predictor of outcome in long-term
Given the paucity of outcome data in adult medullo- follow-up by Brandes et al.4,13
blastoma, comparing the results of E4397 with those of the Another important design issue relevant to the pediatric-
pediatric trials is valuable. However, a number of issues that adult comparison is chemotherapy dosing. The dosing used in
limit these comparisons deserve special attention including E4397 was lower than that used in pediatric trials of similar
biological differences in the neoplasms of these age groups, regimens by 30% for cisplatin, cyclophosphamide, and etopo-
study design issues, and treatment differences. In regard to side. This was based on single institution experience that
biological differences, Group 3 and Group 4 have the poorest included children and adults using this regimen.15,16 Although
prognosis, 40% and 75% 5-year survival respectively, and both dosing differences weaken comparisons between the different
tend to metastasize. Group 3 is rare in adults, whereas Group 4 age groups, the need for dose modification in adults is well
accounts for 25%. Of the more favorable subgroups WNT known. Greenberg et al24 observed greater toxicities in adults
comprises 15% and SHH 60% of adult patients.9,13,38 Group 3 treated with pediatric medulloblastoma chemotherapy protocols.
and Group 4 are likely overrepresented in high-risk cohorts Dose reductions are commonly required in both pediatric and
such as that of our trial. However, E4397 antedated the current adult postradiation maintenance chemotherapy.34,40 Notably, the
molecular characterization of medulloblastoma, and unfortu- incidence of ototoxicity in E4397 was much lower than that seen
nately we are unable to retroactively assess these molecular in trials using postradiation cisplatin. The incidence of neuro-
characteristics. pathy, largely attributed to vincristine, was also much lower.40
Regarding trial design, clinical criteria for risk strat- Even with these limitations the current trends in adult
ification are fundamental to medulloblastoma trials. At the medulloblastoma therapy continue to be based heavily on
time of development of E4397 the significance of residual inference from pediatric observations. For example, the use of

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 Moots et al American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2016

lower dose CSI and adjuvant chemotherapy for standard-risk 6. Evans AE, Jenkin RD, Sposto R, et al. The treatment of
adult medulloblastoma patients is now common despite the medulloblastoma. Results of a prospective randomized trial of
lack of validation in adults.41 To the extent that E4397 sug- radiation therapy, with and without CCNU, vincristine and
gests a lower efficacy for chemotherapy in adults, these prednisone. J Neurosurg. 1990;72:572–582.
7. Tait DM, Thornton-Jones H, Bloom HJG, et al. Adjuvant
inferences must be made in a qualified manner.
chemotherapy for medulloblastoma: the first multicentre control
trial of the International Society of Pediatric Oncology (SIOP I).
Eur J Cancer. 1990;26:464–469.
CONCLUSIONS 8. Zeltzer PM, Boyett JM, Finlay JL, et al. Metastasis stage, adjuvant
E4397 demonstrates prospectively the feasibility and treatment and residual tumor are prognostic factors for medullo-
blastoma in children: conclusions from the Children’s Cancer
safety of moderately intensive preradiation chemotherapy for
Group 921 randomized phase III study. J Clin Oncol. 1999;17:
adults with high-risk medulloblastoma. This sequence of
832–845.
therapy did not interfere with completing CSI. The OS 9. Korshunov A, Remke M, Wiebke W, et al. Adult and pediatric
observed in E4397 is comparable with other reports for adult medulloblastoma are genetically distinct and require different
with high-risk medulloblastoma; however, our results do not algorithms for molecular risk stratification. J Clin Oncol. 2010;28:
indicate a therapeutic advantage in utilizing this preradiation 3054–3060.
chemotherapy, although the incidence of ototoxicity and 10. Northcott PA, Hielscher T, Dubuc A, et al. Pediatric and adult
neuropathy was less. The percentage of M + patients is higher sonic hedgehog medulloblastomas are clinically and molecularly
in this trial and in the prospective trial by Brandes and col- distinct. Acta Neuropathol. 2011a;122:231–240.
leagues than in retrospective reports. However, there was little 11. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma
difference in outcome between M + and M0 patients in our comprises four distinct molecular variants. J Clin Oncol.
cohort. Viewed in conjunction with negative trials of pre- 2011b;29:1408–1414.
12. Brandes AA, Franceshci E. Neuro-oncology: genetic variation in
radiation chemotherapy in pediatric medulloblastoma, the pediatric and adult brain tumors. Nat Rev Neurol. 2010;6:653–654.
standard sequence of CSI, typically including concurrent 13. Brandes AA, Bartolotti M, Marucci G, et al. New perspectives in
chemotherapy and postradiation chemotherapy is favored the treatment of adult medulloblastoma in the era of molecular
for adult high-risk medulloblastoma patients; a recommend- oncology. Crit Rev Oncol Hematol. 2015;94:348–359.
ation still largely derived by inference from pediatric 14. Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative
recommendations. chemotherapy and delayed radiation in children less than three
Although small patient numbers and the presence of years of age with malignant brain tumors. N Eng J Med. 1993;328:
inevaluable patients limit our conclusions, the comparatively 1725–1731.
low OR to preradiation chemotherapy raises an important 15. Jennings MT, Cmelak A, Johnson MD, et al. Differential
question about the efficacy of chemotherapy in adults with responsiveness among “high risk” pediatric brain tumors in a
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