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Journal of Pediatric Surgery 51 (2016) 16651669

Contents lists available at ScienceDirect

Journal of Pediatric Surgery


journal homepage: www.elsevier.com/locate/jpedsurg

The optimal timing of surgical resection in high-risk neuroblastoma


Yesenia Rojas a, Sergio Jaramillo b, Karen Lyons c, Nadia Mahmood c, Meng-Fen Wu d, Hao Liu d,
Sanjeev A. Vasudevan a, R. Paul Guillerman c, Chrystal U. Louis e, Heidi V. Russell e,
Jed G. Nuchtern a,1, Eugene S. Kim a,f,,1
a
Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
b
Department of Radiation Oncology, Baylor College of Medicine, Houston, TX
c
Department of Radiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
d
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX
e
Section of Hematology-Oncology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX
f
Division of Pediatric Surgery, Department of Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA

a r t i c l e i n f o a b s t r a c t

Article history: Background: While most high-risk neuroblastoma (HRNB) patients are enrolled in cooperative group or
Received 17 January 2016 institutional protocols, variability exists within these protocols as to when surgical resection of the primary
Received in revised form 20 May 2016 tumor should be performed after neoadjuvant induction chemotherapy. We sought to determine if the number
Accepted 30 May 2016 of chemotherapy cycles prior to surgery affects surgical or survival outcomes in HRNB patients.
Methods: We performed a retrospective review of all HRNB patients b 18 years of age from 2000 to 2010, at
Key words:
Texas Children's Hospital. Patients were stratied based on the number of neoadjuvant induction chemotherapy
High-risk neuroblastoma
Induction chemotherapy
cycles prior to surgical resection. Pre and post- chemotherapy tumor size, MYCN status, iodine-131-
Surgical resection metaiodobenzylguanidine (MIBG) score at diagnosis, extent of surgical resection, estimated surgical blood loss,
post-operative outcomes, and event free (EFS) and overall survival (OS) were evaluated. Data were analyzed
using Wilcoxon rank-sum test, KruskalWallis test, Fisher's exact test, KaplanMeier analyses, and Cox regres-
sion analyses. P-value b 0.05 was considered signicant.
Results: Data from 50 patients with HRNB were analyzed. Patients were stratied by the number of cycles of
chemotherapy received prior to surgery. Six patients received 2 cycles of chemotherapy (12%), 20 patients re-
ceived 3 cycles (40%), 13 patients received 4 cycles (26%), and 11 patients received 5 cycles (22%) prior to surgical
resection of the primary tumor. The 5-year OS was 33%, 45%, 83% and 36% in patients who received 2, 3, 4 and
5 cycles of chemotherapy prior to surgery, respectively (p = 0.07). Multivariate analysis revealed that patients
who received 4 cycles of chemotherapy had a signicantly lower mortality (HR: 0.11, 95% CI: 0.010.87, p =
0.04) compared to those with 2 cycles of chemotherapy. Among the different cohorts, there were no differences
with respect to MYCN status, MIBG score at diagnosis, incidence of bone marrow metastasis, extent of surgical
resection, estimated blood loss, incidence of post-operative complications, or length of stay.
Conclusion: HRNB patients who receive 4 cycles of chemotherapy prior to surgical resection have a superior OS
than patients who receive 2. Based on the superior survival of patients who received 4 cycles of chemotherapy
prior to surgery, further studies are warranted to elucidate these differences.
2016 Elsevier Inc. All rights reserved.

Neuroblastoma is the most common extracranial solid tumor in chil- for rapid progression and relapse [2]. Despite multimodal therapy, 50%
dren, arising from neural crest cells that differentiate to the sympathetic of patients with newly diagnosed HRNB, and less than 10% of patients
ganglia and adrenal medulla [1]. It accounts for 7% of all malignancies in with relapsed HRNB, will survive [1].
children and 1015% of cancer-related deaths in childhood [1,2]. NB is a Current therapy for HRNB consists of some combination of intensive
heterogeneous disease, and its clinical course can range from spontane- multi-agent induction chemotherapy, surgery, radiation, myeloablative
ous regression to very aggressive, metastatic and progressive disease. consolidation therapy with stem cell rescue and transplantation, 13-cis
Patients with high-risk neuroblastoma (HRNB) are at an increased risk retinoic acid and immunotherapy [14]. The role of surgical resection of
the primary tumor in HRNB is controversial with conicting studies in
the literature regarding the benet of aggressive surgery in this group
Corresponding author at: Children's Hospital Los Angeles, 4650 Sunset Blvd, MS# 100,
Los Angeles, CA 90027. Tel.: +1 323 361 8332; fax: +1 323 361 3534.
[5,6]. Currently, the Children's Oncology Group (COG) recommends ag-
E-mail addresses: eugeneskim@chla.usc.edu, ek49@yahoo.com (E.S. Kim). gressive surgical resection of the primary tumor with the goal of gross
1
Denotes co-senior authors. total resection [2,7]. This current recommendation is supported by the

http://dx.doi.org/10.1016/j.jpedsurg.2016.05.021
0022-3468/ 2016 Elsevier Inc. All rights reserved.
1666 Y. Rojas et al. / Journal of Pediatric Surgery 51 (2016) 16651669

recent results of two studies from the COG and the International Society chemotherapy regimens used at our institution: PEPI (an institutional
of Pediatric Oncology Europe Neuroblastoma (SIPOEN), which demon- review board approved [IRB] Phase II institutional research protocol)
strated benet and improved survival with gross total resection [7,8]. and COG ANBL00P1. The treatment protocol offered to each patient
However, unlike the treatment of other pediatric solid tumors, such as was dependent on which protocol was open or the institutional
rhabdomyosarcoma and Ewing's sarcoma, which clearly dene when standard at the time of patient presentation. The PEPI induction
surgery and radiation should occur, the optimal timing for surgical re- chemotherapy protocol used a combination of cisplatin, etoposide, cy-
section in HRNB has not been well dened, and thus the decision is clophosphamide, and doxorubicin. ANBL00P1 consisted of vincristine,
left to the discretion of individual oncologists and surgeons. At different ifosfamide, and carboplatin, in addition to those used in the PEPI
institutions, some patients may undergo surgery after the last cycle of protocol. Patients were placed on an individualized protocol with dose
induction chemotherapy, while others advocate for an earlier surgical reduction of either PEPI or ANBL00P1 chemotherapy agents if they dem-
intervention, based on when the tumor appears resectable on imaging onstrated renal or organ dysfunction and/or drug toxicity. All induction
[9]. The purpose of this study was to determine if the number of chemo- protocols in this study were a total of 5 cycles. Surgical resection of the
therapy cycles prior to surgical resection affects surgical or survival out- primary tumor was performed by one of two experienced pediatric sur-
comes in HRNB patients. Our hypothesis is that patients treated with geons at our institution. The goal of surgery for all cases was complete
less neoadjuvant chemotherapy would have larger pre-resection tu- resection, dened as removal of N90% of gross total tumor volume.
mors, more difcult resections and thus higher post-operative compli- The extent of tumor resection was determined by the surgeon's opera-
cation rates and worse overall survival. tive report. The decision to operate was made by multi-disciplinary con-
sensus based on imaging and efcacy of chemotherapy, such that
1. Methods patients who did not appear to have signicant tumor reduction with
additional chemotherapy cycles underwent surgical resection. Surgical
1.1. Patients and study design resection after cycle 25 was allowed for patients enrolled on PEPI,
after cycle 4 or 5 if patients were enrolled on ANLB00P1 and at the dis-
This is a retrospective study of all patients 18 years of age diag- cretion of the multidisciplinary team for all patients not enrolled on a
nosed with HRNB at our institution from 2000 to 2010. Patients were in- clinical trial.
cluded if they were 18 years of age, had a diagnosis of HRNB based on
the Children's Oncology Group (COG) risk stratication and underwent 1.4. Metaiodobenzylguanidine (MIBG) scoring system
surgical resection of their primary tumor.
Our study focused on HRNB patients who presented with The scoring method for MIBG scans performed at the time of diagno-
unresectable primary tumors at diagnosis. Patients (n = 10) with re- sis was based on criteria outlined by Messina et al. [13]. The patient's
sectable tumors who did not receive neoadjuvant chemotherapy prior skeleton was divided into 9 segments to assess bone lesions and a
to surgery were excluded. The upfront resection patients presented 10th segment to assess soft tissue involvement [13]. Extension and in-
with smaller tumors (mean 5.0 cm greatest diameter) at the time of di- tensity scores were assigned to each segment to quantify the extent
agnosis and were resected prior to receiving any chemotherapy. In addi- and degree of MIBG uptake. Extension score was graded as follows: 0,
tion, patients with no primary tumor (n = 2) and patients who no sites per segment; 1, one site per segment; 2, more than one site
underwent surgical resection of the primary tumor at another facility per segment; and 3, diffuse involvement (N50% of the segment). Inten-
(n = 9) were excluded from this analysis. Moreover, a patient with a si- sity score was graded as follows: 0, no uptake; 1, doubtful uptake; 2, ob-
multaneous diagnosis of Ewing's sarcoma and HRNB, a patient who had vious uptake; and 3, strong uptake. The maximum extension and
no chemotherapy treatment because of pre-existing cardiomyopathy, intensity scores are 30 and 30, respectively. All MIBG scans were
and a patient with incomplete medical records were excluded. reviewed and scored by a pediatric radiologist (N.M.) blinded to the
patient's outcome.
1.2. Data collection
1.5. Tumor volumes
All clinical data were obtained from electronic and paper medical re-
cords. Collected variables included patient demographics, age at the To determine the extent of tumor reduction with chemotherapy,
time of diagnosis, stage based on the International Neuroblastoma Stag- computed tomography (CT) scans at the time of diagnosis and prior to
ing System (INSS) [10], International Neuroblastoma Risk Group (INRG) surgery were reviewed by a pediatric radiologist (K.L.) blinded to the
stage [11,12], MYCN status, Shimada histology, bone marrow status number of chemotherapy cycles of each patient at the time of the
at diagnosis, MIBG score [13] at the time of diagnosis, induction scan. Tumor volume (cm3) was calculated using the following formula:
chemotherapy protocol, number of chemotherapy cycles prior to surgi- maximal orthogonal tumor length width height 0.52 (/6). Tumor
cal resection of primary tumor, tumor volume reduction, extent of re- volume reduction was calculated as the difference between tumor vol-
section, estimated blood loss (EBL), intraoperative and post-operative ume at the time of diagnosis and prior to surgery.
complications, length of hospital stay, and status at the end of follow-
up. Minor post-operative complications included post-operative fever, 1.6. Statistical analyses
Horner's syndrome, hypovolemia, and ileus. Major post-operative com-
plications included chylous ascites or chylothorax, post-operative hem- Patients were stratied by the number of chemotherapy cycles re-
orrhage (dened as loss of N30% blood volume), bacteremia, adrenal ceived prior to surgical resection. As the HRNB patients represented
insufciency and death. unresectable tumors at the time of diagnosis, and since none of the pa-
tients underwent one cycle of chemotherapy prior to surgical resection,
1.3. Treatment protocols and surgery the 2 cycle group serves as our minimum chemotherapy control group,
and cohorts of patients who received additional cycles of chemotherapy
All patients in this study were treated with a multidisciplinary were compared to this group. Data were summarized and compared be-
approach that consisted of high-dose chemotherapy, surgery, radiother- tween groups using non-parametric Wilcoxon rank-sum test or
apy, autologous stem cell transplantation, and 13-cis retinoic acid. KruskalWallis test for continuous variables and Fisher's exact test for
Two patients from this cohort were treated on the COG ANBL0032 categorical variables. KaplanMeier analyses were used to estimate
study evaluating chimeric 14.18 immunotherapy with 13-cis retinoic overall survival (OS) and event free survival (EFS). Cox regression anal-
acid. The time period of this study spanned 2 different induction yses were performed to determine the association between the number
Y. Rojas et al. / Journal of Pediatric Surgery 51 (2016) 16651669 1667

of chemotherapy cycles prior to surgical resection and survival additional cycles of chemotherapy. Response to chemotherapy was
outcomes after adjusting for other covariates. A P-value b 0.05 was con- the greatest after 2 cycles, which was the minimum number of chemo-
sidered signicant. Analyses were conducted using SAS for Windows therapy cycles patients received in our study. Tumor volume reduction
(SAS Institute, Cary, North Carolina). after 2 cycles of chemotherapy was 77% from the time of diagnosis. After
2 cycles, tumor reduction was increased by 23% more with each
1.7. Ethics and policy succeeding treatment cycle, however this was not statistically signi-
cant (p = 0.27).
This study was approved by the IRB at Baylor College of Medicine (H- There was a signicant difference in the type of induction chemo-
30850). therapy protocol across the groups with more patients who had surgery
after cycles 2 and 3 being treated with the institutional PEPI protocol
2. Results and more patients who underwent surgical resection after cycles 4
and 5 on the COG ANBL00P1 protocol (p = 0.01). Two patients treated
2.1. Patient demographics and clinical presentation on individualized protocols were in the 5-cycle group, as compared to
none in the other groups. Patients who underwent surgical resection
Fifty patients who met inclusion criteria were treated at our institu- after 2 cycles of chemotherapy had the greatest median blood loss
tion between 2000 and 2010. The median age of diagnosis was 2 years when compared to the other groups.
(range 5 months9 years); 54% (n = 27) were male and 46% (n =
23) were female. The majority of the patients (84%) were INSS stage 4 2.2. Survival analyses
and the remaining patients were stage 3 (16%). All of the patients had
unresectable tumors at the time of diagnosis with the majority of pa- The 5-year OS for our cohort, all cycles, of high-risk neuroblastoma
tients presenting with an adrenal primary tumor (n = 40, 80%), follow- patients at our institution was 40%. When stratied by number of cycles
ed by abdominal non-adrenal primary tumor (n = 7, 14%), and thoracic of chemotherapy, the 5-year OS for patients who received 2, 3, 4, and
primary tumor (n = 3, 6%). At presentation, 33 (66%) had metastatic 5 cycles of chemotherapy prior to surgical resection was 33%, 45%,
disease with bone marrow inltration. Bone marrow metastasis was 83%, and 36%, respectively (p = 0.07) (Fig. 1).
negative in 15 (30%) patients and unknown in 2 (4%). Using uorescent By univariate analysis (Table 2), patients treated with 4 cycles of
in situ hybridization (FISH), MYCN amplication was present in 32 chemotherapy prior to surgical resection had a signicantly superior
(64%) patients, unknown in 2 cases (4%), and non-amplied in 16 (32%). OS compared to patients who received 2 cycles (OS HR: 0.19, 95% CI:
Surgical resection of the primary tumor was performed in 6 patients 0.040.85, p = 0.03). The EFS was also superior but not signicant
after cycle 2 (12%), 20 after cycle 3 (40%), 13 after cycle 4 (26%), and 11 (EFS HR: 0.38, 95% CI: 0.101.41, p = 0.15). Patients who had greater
after cycle 5 (22%). Tumor characteristics and treatment regimens tumor volume reduction by chemotherapy had both superior OS (HR:
across the different chemotherapy cycle groups are summarized in 0.98, 95% CI: 0.971.0, p = 0.01) and EFS (HR: 0.98, 95% CI: 0.970.99,
Table 1. The various cohorts were largely equivalent and did not differ p = 0.001). Pre-operative tumor volume was found to be signicantly
signicantly with respect to MYCN status and MIBG score at the time associated with OS (HR: 1.56, 95% CI: 1.062.30, p = 0.02) and EFS
of diagnosis, and interestingly, did not differ with regards to extent of (HR: 1.81, 95% CI: 1.252.61, p = 0.002) with larger tumor volume
tumor resection, post-operative complications, and length of stay. As portending a worse outcome. The negative prognostic indicator of
anticipated, we observed greater tumor volume reduction with MYCN amplication has been well documented in neuroblastoma [1],

Table 1
Tumor characteristics and treatment regimens across different chemotherapy cycle groups, N = 50.

# Chemotherapy cycles prior to surgery P-value

2 3 4 5
n = 6 (%) n = 20 (%) n = 13 (%) n = 11 (%)

MYCN status
Negative 3(50) 5(25) 5(41.7) 3(30) 0.63
Positive 3(50) 15(75) 7(58.3) 7(70)

MIBG score at diagnosis


Extension 17.5 (325) 12.5 (126) 13 (018) 4 (212) 0.21
Intensity 19.5 (525) 16 (324) 14.5 (022) 9 (517) 0.46

Protocol type
ANBL00P1 1 (16.7) 17 (85) 10 (76.9) 6 (54.5) 0.01
PEPI 5 (83.3) 3 (15) 3 (23.1) 3 (27.3)
Individual 0 (0) 0 (0) 0 (0) 2 (18.2)
Tumor volume% reduction from diagnosis 77.3 (22.182.2) 79.7 (20.696.6) 83.2 (48.298.4) 85.6 (097.5) 0.27

Extent of resection
N90% 6 (100) 18 (90) 11 (84.6) 7 (100) 0.73
5090% 0 (0) 2 (10) 2 (15.4) 0 (0)
b50% 0 (0) 0 (0) 0 (0) 0 (0)
EBL (cc) 500 (301500) 185 (102000) 200 (30825) 350 (200650) 0.53

Post-op complication
Minor 0 (0) 2 (33.3) 4 (80) 2 (50) 0.12
Major 4 (100) 4 (66.7) 1 (20) 2 (50)

Length of stay
(days) 11.5 (623) 6 (416) 7 (419) 7 (213) 0.16

MIBG - metaiodobenzylguanidine, EBL - estimated blood loss.


KruskalWallis test for continuous variables and Fisher's exact for categorical variables

Negative values indicate tumor increase
1668 Y. Rojas et al. / Journal of Pediatric Surgery 51 (2016) 16651669

1 younger patients having a higher risk of death. A trend towards im-


Overall survival probability P= 0.07
proved OS was observed for patients with greater chemotherapy-
0.8 induced tumor volume reduction (p = 0.09). Preoperative tumor size
was not signicantly associated with OS but was signicantly associated
0.6 with EFS (HR: 1.79, 95% CI: 1.023.12, p = 0.04). Greater extent of sur-
gical resection was not found to be associated with OS and EFS by mul-
0.4
Chemo Cycle tivariate analysis.
2
0.2 3
4
3. Discussion
5
0
0 1 2 3 4 5
The majority of patients with HRNB present with metastatic disease
Year and/or large, inoperable tumors, and thus the goal of induction chemo-
therapy is to decrease the size of the tumor to facilitate denitive, gross
Fig. 1. 5-year overall survival (OS) of high-risk NB patients based on the number of chemo- total resection. According to the Goldie-Coldman hypothesis,
therapy cycles received prior to surgical resection. cytoreductive therapy may decrease the likelihood of developing resis-
tant clones, and hence increase the chance of curability [14]. With this
goal in mind, previous centers have shown that surgical resection of
and patients with MYCN amplication in our study had a trend towards the tumor is feasible after the 2nd cycle of induction chemotherapy;
higher mortality compared to patients with no MYCN amplication however, the majority of patients with HRNB undergo surgery after
(HR: 2.32, 95% CI:0.866.28, p = 0.10). Moreover, similar to recent re- the 5th cycle [9].
ports of improved survival in patients who undergo complete gross Denitive surgery of large tumors in the early cycles of induction
total tumor resection, patients in our study who underwent incomplete chemotherapy has been shown to be feasible and yield gross total resec-
tumor resection (5090%) had a trend towards increased risk of death tion as the greatest tumor reduction occurs after the 2nd or 3rd cycle of
compared to patients who underwent complete gross total tumor resec- chemotherapy but it remains unknown if this earlier resection results in
tion (N 90%), though not reaching statistical signicance (p = 0.58). In improved survival or increased operative complexity [15]. Based on our
addition, we did not observe a statistically signicant difference in sur- cohort of patients, we found no signicant differences in the extent of
vival with regards to age, post-operative complications, length of hospi- tumor resection across the 4 chemotherapy groups. From our data, in-
tal stay, or based on the chemotherapy protocol received. creased tumor reduction with additional cycles of chemotherapy did
By multivariate analysis, patients who received 4 cycles of chemo- not necessarily translate into an increased likelihood of gross total re-
therapy had a signicantly improved OS compared to patients who re- section. Additionally, patients who received only 2 or 3 cycles of chemo-
ceived 2 cycles after adjusting for other variables (OS HR: 0.11, 95% CI: therapy were just as likely to have N 90% tumor resection as those
0.010.87, p = 0.04). The EFS was also superior but not signicant treated with 4 or 5 cycles. However, patients who underwent resection
(EFS HR: 0.5, 95% CI: 0.112.34, p = 0.38)(Table 3). Patients with after 2 cycles of chemotherapy were more likely to have increased blood
MYCN amplied tumors had a signicantly worse OS (HR: 3.6, 95% CI: loss during surgery, which is likely related to the larger tumor size.
1.2410.46, p = 0.02) and a trend towards worse EFS (HR: 2.53, 95% Moreover, the length of post-operative hospital stay did not signicant-
CI: 0.956.76, p = 0.06) when compared to those with non-MYCN ly differ among the groups.
amplied tumors. Age was found to be related to OS (p = 0.06) with To address our hypothesis, patients who underwent early surgical
resection following 2 cycles of chemotherapy did not result in superior
survival but rather had the worst OS when compared to patients who
Table 2 received 3, 4, and 5 cycles. Interestingly, patients with the best OS
Univariate analyses for overall survival (OS) and event free survival (EFS).
(83%) were those who underwent surgery after 4 cycles of chemother-
Overall survival (OS) Event free survival (EFS) apy. One may postulate that the patients resected after 4 cycles either
HR 95% CI P HR 95% CI P had biologically different disease and/or a different disease burden at

Chemotherapy cycle
2 1 1
Table 3
3 0.51 0.161.64 0.25 0.77 0.252.36 0.64
Multivariate analyses for overall survival (OS) and event free survival (EFS).
4 0.19 0.040.85 0.03 0.38 0.101.41 0.15
5 0.85 0.032.88 0.79 0.80 0.242.66 0.71 Overall survival (OS) Event free survival
(EFS)
MYCN status
Negative 1 1 HR 95% CI P HR 95% CI P
Positive 2.32 0.866.28 0.09 2.23 0.905.55 0.08
Chemotherapy cycle
Protocol type 2 1 1
ANBL00P1 0.59 0.251.41 0.23 0.90 0.411.98 0.80 3 0.45 0.141.48 0.19 0.80 0.262.50 0.71
PEPI 1 1 4 0.11 0.010.87 0.04 0.50 0.112.34 0.38
Individual 0.57 0.074.55 0.59 0.52 0.074.09 0.53 5 1.72 0.456.56 0.43 0.87 0.233.29 0.84
Tumor reduction 0.98 0.971.00 0.01 0.98 0.970.99 0.001
Pre-op tumor volume (cm3) 1.56 1.062.30 0.02 1.81 1.252.61 0.001 MYCN status
Negative 1 1
Extent of resection Positive 3.60 1.2410.46 0.02 2.53 0.956.76 0.06
N90% 1 1 Tumor reduction % 0.98 0.961.00 0.09 0.99 0.981.01 0.42
5090% 1.51 0.356.52 0.58 1.03 0.244.35 0.97 Pre-op tumor volume (cm3) 1.43 0.802.57 0.23 1.79 1.023.12 0.04

Post-op complications Extent of resection


Minor 1 1 N90% 1 1
Major 1.62 0.475.57 0.44 1.92 0.645.80 0.25 5090% 1.65 0.2311.85 0.62 0.52 0.093.02 0.46
Length of stay 1.05 0.961.15 0.28 1.05 0.971.13 0.20 Age, month 0.98 0.951.00 0.06 0.99 0.971.01 0.31
Cycle 2 group is reference group as we hypothesized that patients treated with less Cycle 2 group is reference group as we hypothesized that patients treated with less
chemotherapy would have worse overall survival. chemotherapy would have worse overall survival.
Log scale Log scale
Y. Rojas et al. / Journal of Pediatric Surgery 51 (2016) 16651669 1669

the time of diagnosis based on the differences in survival. But, as shown institution, which favored earlier resection during this study period, a
in Table 1, we found no signicant differences identied with respect to patient who received 5 cycles of chemotherapy prior to surgery would
MYCN status and extent of disease at diagnosis, as determined by MIBG imply a particularly invasive tumor that had a poor response or a patient
score, to explain the differences observed in survival. Furthermore, by with a number of complications and infections.
multivariate analysis, MYCN status and the number of presurgical che- With regards to the improved survival seen in the 4-cycle patients,
motherapy cycles were the only independent prognostic factors of over- one hypothesis could be the potential positive impact of post-
all survival, with MYCN non-amplied patients and 4-cycle patients operative clean-up chemotherapy. Patients resected after 4 cycles
demonstrating a decreased risk of death. may have received the greatest possible tumor reduction benet from
Our study has a number of limitations, which include the retrospec- chemotherapy before resection and then an additional benet from
tive nature of the data, the small number of patients in each chemother- the last clean-up cycle as the minimal residual post-surgical disease
apy cycle group, and the different chemotherapy protocols used during burden would have been very small.
the study period. Although our institution is a high-volume center in the Induction chemotherapy in HRNB decreases tumor burden and facil-
treatment of neuroblastoma, the low incidence of the disease makes it itates surgical resection; however, there appears to be a tipping point in
challenging to acquire signicant numbers from a single institution. Fu- which more chemotherapy may result in poorer survival. Despite the
ture multi-centered, cooperative group studies are needed to better limitations of our study, the observed superior survival of patients
study this question with larger numbers of patients. In addition, our who underwent surgical resection after 4 cycles of induction chemo-
nding of superior survival in patients who received 4 cycles of chemo- therapy suggests timing of surgery may play a crucial role in the long-
therapy prior to surgery is based on the assumption that all patients in term survival of HRNB patients. As is currently practiced in other pedi-
this study are inherently similar at the time of diagnosis and in their re- atric solid tumors such as rhabdomyosarcoma, Ewing's sarcoma, and
sponse to chemotherapy. However, these patients may have subtle un- Wilms tumor, future COG protocols for HRNB should consider standard-
accounted differences, which may account for the differences in survival ized timing for surgical resection during induction chemotherapy based
but were not detected by statistical analyses based on the small cohorts. on the results of prospective trials.
Another potential confounding factor is the variability in the treatment
protocol, as not all patients studied received the same chemotherapy
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