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Comparison for efficacy and toxicity in 2 vs 3 cycles of cisplatin consolidation therapy in children nasopharyngeal carcinoma
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Comparison for efficacy and toxicity in 2 vs 3 cycles of cisplatin consolidation therapy in children nasopharyngeal carcinoma
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Content
Comparison for Efficacy and Toxicity in 2 vs 3 Cycles of Cisplatin Consolidation Therapy in
Children Nasopharyngeal Carcinoma
by
Amei Hao
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
BIOSTATISTICS
December 2021
Copyright 2021 Amei Hao
ii
Acknowledgements
I would like to express my gratefulness for my thesis advisor Dr. Jin Piao, thanks for her
dedicated academic guidance and patience. She is always a caring, helpful mentor to me. Thanks
her for introducing me to Children’s Oncology Group ARAR0331 study. Also, I want to express
my feeling of gratitude to my thesis committee members: Dr. Donald Barkauskas and Dr. Ha Dang.
Appreciate their valuable suggestions and thoughts.
iii
Table of Contents
Acknowledgements ii
List of Tables iv
List of Figures v
Abstract vi
1. Introduction 1
1.1 Disease Background ……………………………………………………………………….. 1
1.2 Treatment of NPC and Experimental Design Schema …………………………………....... 2
2. Data and Methods 4
2.1 Data …………………………………………………………………………………….…... 4
2.1.1 Patient Eligibility …………………………………………………………………...... 4
2.1.2 Patients Demographic Characteristics ……………………….………………………. 4
2.1.3 Protocol treatment description .………………………………….…………………… 5
2.1.4 Outcome data………………………………….…………….……………………….. 5
2.2 Methods…………………………………………………………………………………….. 6
3. Results 8
3.1 Exploratory Analysis of Baseline Patient Characteristics…………………………………. 8
3.2 Kaplan-Meier Method based on different treatment cycles…………………………….….. 9
3.3 Toxicity Analysis…………………………………………………………………………. 11
3.4 Cox Proportional-Hazard Models for Potential Risk Factors for EFS and OS……………. 13
Discussions 16
References 18
iv
List of Tables
1. Descriptive Patient Characteristics of the NPC Study Cohort among two-cycle of cisplatin
and three-cycle of cisplatin……………………………………....……………………... 8
2. Log-Rank Test Comparing Survival Outcomes between the Two and Three-Cycle of
Cisplatin Treatments……………………………………………………………………. 11
3. Grade 3 or Higher Adverse Events with CTCAE version 4 by Organ System and Toxicity
Type among NPC Patients with two treatment regimens…………………………….…. 12
4. Univariate Cox Proportional-Hazards Analysis of Risk Factors for EFS among NPC
Patients…………………………………………………………………………………. 14
5. Univariate Cox Proportional-Hazards Analysis of Risk Factors for OS among NPC
Patients…………………………………………………………………………………. 14
6. Univariate Cox Proportional-Hazards Analysis in Cisplatin Cycles for OS and EFS among
NPC Patients……………………………………………………………………………. 15
7. Log Rank Test for All Patients by AJCC Stages for OS and EFS………………...…….. 15
v
List of Figures
1. Study Design Schema of the ARAR0331 Trial…………………………..……………….. 3
2. The Kaplan-Meier Estimate Curves of Event-Free Survival (EFS) Estimated Proportion by
Different Cycles of Consolidation Treatment……………………………….…………... 10
3. The Kaplan-Meier Estimate Curves of Overall Survival (OS) Estimated Proportion by
Different Cycles of Consolidation Treatment ………………………….……………….. 10
vi
Abstract
Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCR) are the main
effective treatments for childhood nasopharyngeal carcinoma (NPC). The incidence in children is
rare in the United States. The Children’s Oncology Group ARAR0331 protocol was initially
designed as three cycles of cisplatin during 6 weeks of radiation. However, the intolerant event led
to a delay in chemotherapy that made three cycles of cisplatin impossible to administer within the
6–7-weeks radiotherapy. Therefore, the protocol was redesigned to only two cycles of cisplatin
during radiotherapy. This study includes 105 Stratum B (stages IIb – IV) participants with NPC.
The average age of the patients was 14 years old, and 48.57% were African American. The primary
purpose of this thesis is to compare the efficacy and toxicity between two and three cycles of
cisplatin consolidation therapy in patients with NPC enrolled in the American Joint Committee
(AJCC) with stage IIb to stage IV cancer. Participants with NPC were evaluated for their tolerance
to three cycles of cisplatin, and the study committee decided to omit one cycle of cisplatin due to
the intolerability events. To investigate the efficacy of reduced cisplatin treatment during the
consolidation therapy on survival outcomes, participants with three cycles of cisplatin in CCR (n
= 44) or two cycles of cisplatin in CCR (n = 61) were divided into two groups. The Kaplan-Meier
method was used to estimate the survival function, and the primary outcomes were event-free
survival (EFS) and overall survival (OS). For the EFS events, the 5-year survival estimation for
81.0% (95% CI: 68.2% ,89.0%) for the two-cycle CCR treatment group, versus three- cycle CCR
treatment was 90.8% (95% confidence interval [CI]: 77.3%, 96.4%, Hazard Ratio (HR)= 55.5%)
(P= 0.268), the hazard ratio of 55.5% told us that the hazard rate in the for three-cycle CCR
treatment group is 0.555 times of that in the two-cycle group. For the OS events, the 5-year survival
estimation for two-cycle CCR treatment was 91.4% (95% CI: 80.6%, 96.3%), versus 92.1% (95%
vii
CI: 77.3%, 97.4%, HR= 71.1%) for the three-cycle CCR treatment group (P= 0.578), the hazard
ratio of 71.1% told us that the hazard rate in the for three- cycle CCR treatment group is 0.711
times of that in the two-cycle group. Toxicity analysis indicated that 34 patients (55.7%)
experienced adverse events (AEs) classified as grades 3, 4 or both in two-cycle group, and 41
patients (93.2%) experienced AEs in three-cycle group. Total 75 out of 105 patients (71.4%)
suffered from AEs, including 55.7% of patients who experienced an AE of grade 3 or higher
toxicity in the two-cycle cohort compared to 93.2% of patients who experienced AEs in three-
cycle cohort. This study showed a decreased tendency of EFS for the patients who were given
fewer cisplatin doses during CCR. In the meanwhile, patients in three-cycle cisplatin group
compared to two-cycle cisplatin group had a more frequent occurrence of AEs.
1
1. Introduction
1.1 Disease Background
Nasopharyngeal carcinoma (NPC) is a cancer that is known to arise in the nasopharynx. It
is one of the commonly malignant tumors in Southeast Asia and Africa and has attracted
considerable attention in the medical community (Ellen & Hans-Olov, 2006). NPC can affect
people at any age and is commonly observed in the fifth and sixth decades of life. The nasopharynx
has a well-developed vascular and lymphatic systems. The path of tumor spread, symptomatology,
and therapeutic regimen are all determined by these characteristics. Early symptoms of NPC
include nosebleeds, congestion, and otitis media. This malignancy is extremely rare in children. In
the United States, the incidence of childhood NPC is about 1 to 1.5 cases per million annually
(Iyad et al., 2010).
Most patients diagnosed are adolescent male children. NPC is more pervasive
in Black children in the United States and is currently under investigation. It is primarily associated
with the Epstein–Barr virus (Lawrence & Christopher, 2014).
Because of the complex anatomical site, NPC is considered unresectable. As a matter of
fact, NPC is very sensitive to radiation therapy, which has become the standard treatment. To
achieve a good locoregional control, high doses (generally >65 Gy) are necessary (Carlos et al.,
2019). The treatment protocol for childhood NPC has traditionally consisted of induction
chemotherapy (IC), which reduces both the tumor size and clinical symptoms in the short term.
Medical researchers have achieved positive results in previous trials by using IC to minimize
radiation. One study demonstrated that nearly 60% to 80% of patients have achieved long-term
survival (Daniel et al., 2010).
Based on the efficiency of concurrent chemoradiotherapy (CCR)
2
regimens in recent years, the treatment of NPC in children has developed to integrate this regimen
(Wei-Xiong et al., 2021).
1.2 Treatment of NPC and Experimental Design Schema
In one account of the Children’s Oncology Group (COG) ARAR0331 trial
(ClinicalTrials.gov Identifier: NCT00274937), the American Joint Committee on Cancer (AJCC)
stipulates stages for 111 assessable NPC patients (Carlos, 2013). Patients with baseline Stages IIb
to IV are recommended to undergo three cycles of IC with cisplatin and fluorouracil, and a total
of three cycles of cisplatin during CCR followed IC. The ARAR0331 trial aimed to assess the
effects of IC and CCR. The ARAR0331 is a prospective study that mainly measures two outcomes,
including the timeline from study entry to progression of the disease, a second malignant tumor
diagnosis, death, or last follow-up as a 5-year event-free survival (EFS) and the timeline from
study entry to death despite reason, or follow-up as an overall survival (OS) (Carlos et al., 2019).
ARAR0331 evaluated the feasibility of treatment options for the first 21 evaluable patients with
NPC. The results showed that 9 patients experienced intolerance events (including severe anorexia,
dysphagia, and mucositis) and consequently required a reduction in the cisplatin dosage. These
events delayed the chemotherapy schedule, and the three cycles of cisplatin could not be completed
within the prescribed 6-7 weeks. Therefore, in the revised study, modification of the consolidation
therapy was recommended by omitting the last cycle of the cisplatin, which provided an
opportunity to determine a more suitable treatments regimen for future clinical outcomes.
In this study, we use the data from ARAR0331 to describe the characteristics and survival
probabilities of patients with different cycles of cisplatin dosage during CCR. Moreover, we
3
compared the toxicity and efficacy between the two-cycle and three-cycle of cisplatin regimens
during the consolidation therapy phase in children with NPC who are alive after induction therapy.
The experimental design schema is shown in Figure 1 (Carlos et al., 2019):
Figure 1: Study Design Schema of the ARAR0331 Trial (XRT and Radiation Therapy
Classification System)
4
2. Data and Methods
2.1 Data
2.1.1 Patient Eligibility
A total of 111 patients were enrolled in ARAR0331 to receive IC and two or three cycles
of consolidation therapy between February 2006 and January 2012. According to the Pediatric
Central Institutional Review Board of the National Cancer Institute and the institutional review
boards of engaging organizations, all underage participants required permission from guardians to
participate in the trial (Carlos et al., 2019). Patients who only underwent the induction phase were
excluded from this study.
2.1.2 Patients Demographic Characteristics
Patients in Stratum B (Stages IIb, III and IV) were recruited for this study, and Stratum A
patients were excluded. The demographic characteristics of participants with NPC consisted of age
at study entry, gender, race, and ethnicity. Participants were under the age of 19 with histology
type II or III (according to WHO classification). Age (in years) at enrollment was considered as a
continuous feature. Gender was identified as a binary variable: male or female. Race was
categorized into three groups: Black or African American, White, and Other/Unknown. Ethnicity
was grouped into two categories: Hispanic or Latino and Non-Hispanic or Latino. All evaluable
patients had a controllable diagnosis for the disease. Uncontrolled infections and pregnant females
were not included in the research.
5
2.1.3 Protocol treatment description
Stratum B treatment was given to all patients in the AJCC stages IIb to IV at the time of
enrollment. Patients in the AJCC stages IIb to IV were given three cycles of IC with cisplatin and
fluorouracil every 21 days, then assigned a consolidation therapy including radiation therapy,
followed by three cycles of cisplatin every 21 days (Carlos, 2013).
2.1.4 Outcome data
The time from the end of induction to an event of interest (progression of the disease,
diagnosis of a second malignancy, or death), or last follow-up (censored), whichever occurred first,
was defined as Event-free survival (EFS). The time from the end of induction until the event of
death, regardless of the reason or the patient's last recorded contact date with the study, whichever
occurred first, was defined as the overall survival (OS). OS events were implied as a death(event),
and the rest were considered censored observations.
We reported adverse events (AEs) during the clinical trial to protect the safety of patients
enrolled in the study and those who will participate in future studies using similar medications.
AEs data were collected from each reporting block (two-cycle and three-cycle of CCR), including
organ system and toxicity grade (grade 3 or 4), and toxicity type by the Common Terminology
Criteria for Adverse Events version 4 (CTCAE 4). The frequency and percentage of patients with
grade 3 or higher toxicity were reported according to organ systems.
6
2.2 Methods
To investigate the demographic and clinical factors between two-cycle of cisplatin group
and three-cycle of cisplatin group in patients, including the mean or frequency, percentile, or range
for the demographic characteristics, Fisher’s exact tests were applied for the categorical variables.
And for the continuous variable (age at enrollment), an independent t-test was used. The variables
tested included age, gender, race, ethnicity, AJCC stage to find any significant differences between
study groups.
To evaluate the effect of reducing CCR intensity from three cycles of cisplatin to two cycles
of cisplatin on survival outcomes, we included and assessed all eligible patients who had begun
the consolidation therapy in the analysis. The Kaplan-Meier estimates of EFS and OS for both
groups and their corresponding 95% confidence intervals (CIs) were reported. The log-rank test, a
non-parametric statistical test used to investigate the presence of a significant difference between
the two treatment groups, was utilized as the test statistic for the analysis (Vikas et al., 2007). The
null hypothesis was that there is no significant difference between different cycles of treatments
between two and three cycles of cisplatin group patients, and it tested for both EFS and OS.
The summary of toxicity analysis was reported to compare the toxicity between two versus
three cycles of cisplatin consolidation therapy by using Fisher’s exact test. The maximum grade
of every CTACE 4 AE was established for each eligible patient who underwent consolidation
therapy.
7
We used the Cox regression models to assess OS-related and EFS-related potential risk
factors with patients’ demographic characteristics, in which age, gender, race, ethnicity, AJCC
stages were evaluated as covariates. The results of univariate and multivariate models and the
corresponding hazard ratios (HRs) with 95 % CIs were obtained. In the univariate model, p-values
and HRs indicated a relationship between each variable and increased risk of death. Covariates
with p-value under a threshold of 0.05 decided to be included in the multivariate model; otherwise,
the multivariate analysis would not be carried out.
All statistical analyses used two-sided tests with a significant level of 𝛼 = 0.05. SAS,
Python 3 and SPSS Statistics IBM were used. Packages included lifelines, matplotlib, pandas and
numpy.
8
3. Results
3.1 Exploratory Analysis of Baseline Patient Characteristics
There were 111 patients enrolled in ARAR0331, but 6 participants were excluded from
this thesis since they did not receive a consolidation therapy. Table 1 shows the demographic
characteristics of the 105 evaluable patients enrolled during the initial enrollment period and who
received induction and consolidation therapies. A total of 61(58.1%) patients started consolidation
therapy with two cycles of cisplatin, 44 (41.9%) patients started consolidation therapy with three
cycles of cisplatin. The participants ranged in age from 3 to 18 years old. Of the participants in the
cohort study, 69.5% were male, and 30.5% were female participated in the cohort study. The
African Americans made up the largest race group in both groups (two-cycle: 49.2% and three-
cycle 47.7%). Most participants’ ethnicity was non-Hispanic or Latino (two-cycle: 88.5% and
three-cycle: 84.1%). Due to the small population size of the unknown ethnicity (2), the unknowns
were excluded when calculated the p-value. AJCC stage IV was the most common stage diagnosed
at the enrollment. All the pairs of variables showed no significant associations between the two
groups. P-values and more details were presented in Table 1 as follows.
Table 1: Descriptive Patient Characteristics of the NPC Study Cohort among two-cycle of
cisplatin and three-cycle of cisplatin (n =105)
Variables Subjects on 2-cycle cisplatin
n=61 N (%)
Subjects on 3-cycle cisplatin
n=44 N (%)
p-value
Age (years) mean, SD 13.75 (2.92) 14.23 (2.36) 0.351
Gender 0.832
Male 43 (70.5%) 30 (68.2%)
Female 18 (29.5%) 14 (31.8%)
Race 0.801
Black or African American 30 (49.2%) 21 (47.7%)
White 24 (39.3%) 16 (36.4%)
Other/Unknown 7 (11.5%) 7(15.9%)
Ethnicity 0.771
9
Hispanic or Latino 7 (11.5%) 6(13.6%)
Non-Hispanic or Latino 54 (88.5%) 36 (81.8%)
Unknown 0 (0.0%) 2 (4.5%)
AJCC Stage 0.664
IIb 5 (8.2%) 6 (13.6%)
III
IV
23 (37.7%)
33(54.1%)
15 (34.1%)
23(52.3%)
3.2 Kaplan-Meier Method based on different treatment cycles
Figure 2 shows the Kaplan–Meier curves for EFS that estimated the proportion by different
cycles of consolidation treatment. The 105 evaluable patients had a median follow-up of 63 months,
the 5-year EFS for two cycles of cisplatin consolidation therapy and three cycles of cisplatin
consolidation therapy were 81.0% (95% CI: 68.2% ,89.0%), and 90.8% (95% CI: 77.3%, 96.4%),
respectively. Figure 3 shows the Kaplan–Meier estimate curves of OS that estimated the proportion
by different cycles of consolidation treatment. The 5-year OS for two cycles of cisplatin
consolidation therapy and three cycles of cisplatin consolidation therapy were 91.4% (95% CI:
80.6%, 96.3%) and 92.1% (HR= 71.1%, 95% CI: 77.3%, 97.4%), respectively. The probability of
a three-cycle cisplatin consolidation in surviving patients with NPC was higher than the probability
of a two-cycle cisplatin consolidation in surviving patients with NPC by the time changing.
The log-rank tests (Table 2) showed that there were no significant differences in EFS (χ
2
=
1.263, df = 1, p = 0.261) or OS (χ
2
= 0.313, df = 1, p = 0.576). The study failed to reject the null
hypothesis for both survival outcomes. For EFS, the group of patients who received three cycles
of cisplatin (median = 6.7 years) had a longer median survival time than that of the two-cycle
cisplatin group (median = 6.3 years). For OS, the Kaplan-Meier curve showed a similar pattern
with EFS, but the survival estimated proportions were quite close between the 4th and 6th years
10
for both groups. In general, patients had better outcomes in the three-cycle treatment group,
although there was no statistically significant difference at 2-sided alpha=0.05.
Figure 2. The Kaplan-Meier Estimate Curves of Event-Free Survival (EFS) Estimated Proportion
by Different Cycles of Consolidation Treatment
Figure 3. The Kaplan-Meier Estimate Curves of Overall Survival (OS) Estimated Proportion by
Different Cycles of Consolidation Treatment
11
Table 2: Log-Rank Test Comparing Survival Outcomes between the Two and Three-Cycle of
Cisplatin Treatments
Log-Rank Test χ
2
df p-value
EFS 1.263 1 0.261
OS 0.313 1 0.576
3.3 Toxicity Analysis
There were 105 patients included in the analysis to compare grade 3 or higher toxicity
between two and three-cycle of Cisplatin treatments groups. Seventy-five patients (71.4%)
developed at least a Grade 3 or higher toxicity event, including 41 (93.2%) out of 44 patients who
received three cycles of cisplatin as compared with 34 (55.7%) in 61 patients receiving two cycles
of cisplatin. There was a significant difference in AEs between two treatment regimens (p <.001).
Table 3 included the occurrence of Grade 3 or higher AE with CTCAE by organ system groups
and toxicity types. The frequency in the Table 3 recorded the number of unique patients for each
occurrence of toxicity, but one patient may experience multiple toxicities in different organ
systems and toxicity types during the study progress. There were 93.2% of patients in the group
receiving three cycles of cisplatin suffered from grade 3+ AEs, and most AEs occurred in the 3-
cycle group. Mucositis oral was the most common AE that happened to patients in three cycles of
cisplatin group (47.7%). Hearing impaired, lymphocyte count decreased, and neutrophil count
decreased were the most common AEs that happened to patients in two cycles of cisplatin group
(9.8%). Mucositis oral was the most common event in 105 patients (26 patients total, 2-cycle:
8.2%, 3-cycle: 47.7%), with the remaining events having a relatively smaller number of cases.
Table 3 provided more information, including numbers and percentages of patients who had grade
3+ AE across all AE types by group.
12
Table 3: Grade 3 or Higher Adverse Events with CTCAE version 4 by Organ System and
Toxicity Type among NPC Patients with two treatment regimens (n = 105)
Toxicity Type AE with 2-cycle (n = 61)
N (%)
AE with 3-cycle (n = 44)
N (%)
Abdominal infections - 3 (6.8%)
Abdominal pain - 2 (4.6%)
Acidosis - 1 (2.3%)
Acute kidney injury - 3 (6.8%)
Alanine aminotransferase increased 1 (1.6%) 1 (2.3%)
Allergic reaction 1 (1.6%) -
Anemia 1 (1.6%) 8 (18.2%)
Anorexia 4 (6.6%) 15 (34.1%)
Anxiety - 1 (2.3%)
Apnea - 1 (2.3%)
Aspartate aminotransferase increased 1 (1.6%) -
Blood bilirubin increased 1 (1.6%) 1 (2.3%)
Catheter related infection 1 (1.6%) 1 (2.3%)
Cheilitis - 1 (2.3%)
Chronic kidney disease - 2 (4.6%)
Constipation - 4 (9.1%)
Dehydration 3 (4.9%) 12 (27.3%)
Depression 1 (1.6%) -
Dermatitis radiation - 1 (2.3%)
Dry mouth 1 (1.6%) 6 (13.6%)
Dysphagia 4 (6.6%) 7 (15.9%)
Ear and labyrinth disorders 1 (1.6%) -
Edema face - 1 (2.3%)
Epistaxis - 1 (2.3%)
Erythema multiforme 2 (3.3%) -
Esophageal pain 1 (1.6%) 1 (2.3%)
Esophagitis 2 (3.3%) 2 (4.6%)
Eye infection - 1 (2.3%)
Fatigue 1 (1.6%) 4 (9.1%)
Febrile neutropenia - 1 (2.3%)
Fever - 1 (2.3%)
Gastritis - 2 (4.6%)
Generalized muscle weakness - 1 (2.3%)
Headache - 2 (4.6%)
Hearing impaired 6 (9.8%) 6 (13.6%)
Hypercalcemia - 2 (4.6%)
Hyperkalemia 3 (4.9%) 2 (4.56%)
Hypomagnesemia 2 (3.3%) 7 (15.9%)
Hyperuricemia 1 (1.6%) 1 (2.3%)
Hypercalcemia - 2 (4.6%)
Hypokalemia 3 (4.9%) 10 (16.4%)
Hypomagnesemia 2 (3.3%) 7 (15.9%)
Hyponatremia 4 (6.6%) 5 (11.4%)
Hypophosphatemia 2 (3.3%) 8 (18.2%)
Hypotension 1 (1.6%) 2 (4.6%)
Infections and infestations 1 (1.6%) 4 (9.1%)
Investigations - Other, specify 1 (1.6%) -
Laryngeal mucositis - 1 (2.3%)
Lip infection - 1 (2.3%)
Lymphocyte count decreased 6 (9.8%) 6 (13.6%)
13
Mucositis oral 5 (8.2%) 21 (47.7%)
Nausea 5 (8.2%) 20 (45.5%)
Neck pain - 2 (4.5%)
Neutrophil count decreased 6 (9.8%) 19 (43.2%)
Non-cardiac chest pain - 1 (2.3%)
Oral pain 1 (1.6%) 8 (18.2%)
Pain - 1 (2.3%)
Pain of skin - 1 (2.3%)
Peripheral motor neuropathy - 1 (2.3%)
Pharyngeal mucositis - 5 (11.4%)
Pharyngitis - 1 (2.3%)
Pharyngolaryngeal pain - 5 (11.4%)
Radiation recall reaction - 1 (2.3%)
Rash maculopapular - 1 (2.3%)
Renal and urinary disorders 1 (1.6%) 1 (2.3%)
Seizure 2 (3.3%) 1 (2.3%)
Sepsis - 1 (2.3%)
Sinusitis - 1 (2.3%)
Skin infection - 1 (2.3%)
Small intestine infection - 1 (2.3%)
Stevens-Johnson syndrome 1 (1.6%) -
Stomach pain - 1 (2.3%)
Syncope - 2 (4.5%)
Trismus - 2 (4.5%)
Vaginal infection - 1 (2.3%)
Vascular access complication - 1 (2.3%)
Voice alternation - 1 (2.3%)
Vomiting 4 (6.6%) 17 (38.6%)
Weight loss 2 (3.3%) 6 (13.6%)
White blood cell decreased 4 (6.6%) 15 (34.1%)
Total Patients Suffered AEs
P-Value <.001
75
Total Distinct Patients with 2-cycle
(n = 61) N (%)
Total Distinct Patients with 3-cycle
(n = 44) N (%)
34 (55.7%) 41 (93.2%)
3.4 Cox Proportional-Hazard Models for Potential Risk Factors for EFS and OS
The univariate Cox regression models for all potential risk factors(including age, gender,
race, ethnicity, AJCC stage) for EFS and OS are shown in Table 4 and 5. Using Cox proportional
hazard regression, we estimated the baseline characteristics for EFS and OS by different group of
patients. The results in Table 4 indicated the significance of the covariates in predicting the risk of
disease progression or relapse (EFS events). No baseline factors were selected for the multivariate
analysis of the EFS using the Cox proportional-hazard model. Table 5 showed the significance of
the covariates in predicting the risk of death (OS events). And we were unable to identify any
14
significant factors for OS events in this analysis. AJCC IIb stage was excluded from the univariate
analysis for both EFS and OS due to the limited sample size and the lack of a sufficient number of
events (EFS events: 0, OS events:0), which occurred a convergence issue. So we applied a log
rank test for investigating whether AJCC stages affects survival distribution, which tested for
differences between AJCC stages. The p-values indicated that there were no statistically significant
differences regardless of patient enrollment stages for either EFS or OS.
Table 4: Univariate Cox Proportional-Hazards Analysis of Risk Factors for EFS among NPC
Patients
Potential Risk Factors df SE Wald
χ
2
HR (95% CI) p-value
Age (years) 1 0.091 0.192 0.961 (0.805,1.148) 0.662
Gender
Male ref - - - -
Female 1 0.572 0.394 1.432 (0.467,4.394) 0.530
Race
Black ref - - - -
White 1 0.540 1.021 1.726 (0.599,4.976) 0.312
Other 1 0.707 1.026 2.047 (0.512, 8.191) 0.311
Ethnicity
Non-Hispanic or Latino ref - - - -
Hispanic or Latino 1 0.573 2.818 2.615 (0.851,8.036) 0.093
AJCC Stage
IV ref - - - -
III 1 0.508 0.408 0.723 (0.267,1.956) 0.523
IIb 1 - - - -
Table 5: Univariate Cox Proportional-Hazards Analysis of Risk Factors for OS among NPC
Patients
Potential Risk Factors df SE Wald
χ
2
HR (95% CI) p-
value
Age (years) 1 0.115 0.082 1.033 (0.825,1.295) 0.775
Gender
Male ref - - - -
15
Female 1 0.667 0.185 0.751 (0.203,2.775) 0.667
Race
Black ref - - - -
White 1 0.633 1.103 1.225 (0.354, 4.232) 0.749
Other 1 0.837 0.299 1.581 (0.306, 8.162) 0.584
Ethnicity
Non-Hispanic or Latino ref - - - -
Hispanic or Latino 1 0.776 0.230 1.451 (0.317, 6.633) 0.631
AJCC Stage
IV ref - - - -
III 1 0.586 0.001 1.006 (0.319,3.172) 0.991
IIb 1 - - - -
Table 6: Univariate Cox Proportional-Hazards Analysis in Cisplatin Cycles for OS and EFS
among NPC Patients
Outcomes df SE Wald
χ
2
HR (95% CI) p-value
Cisplatin Cycles
OS two ref - - - -
three 1 0.613 0.310 0.711(0.214,2.362) 0.578
Cisplatin Cycles
EFS two ref - - - -
three 1 0.532 1.227 0.555(0.195,1.574) 0.267
Table 7: Log Rank Test for All Patients by AJCC Stages for OS and EFS
Log- Rank Test χ
2
df p-value
OS 1.416 2 0.493
EFS 2.662 2 0.264
16
Discussions
This study mainly explored the differences between efficacy and toxicity in two versus
three cycles of cisplatin consolidation therapy in children with NPC.
We compared outcomes for participants who began consolidation after three (44 patients)
versus two (61 patients) cycles of cisplatin to explore the effect of cisplatin decrease during
consolidation because of the feasibility revision. We discovered a trend toward lower EFS and OS
proportions in patients given fewer cisplatin doses during CCR. The median survival time for the
three-cycle group was longer than that of the two-cycle cisplatin group. Demographics factors,
including age, gender, race, and ethnicity, did not significantly differ between the two research
groups. We then tested the tolerability of patients who received two versus three cycles of cisplatin
treatments. The AEs occurred in 93.2% (41 patients) of the 44 tolerability-evaluable patients who
received three cycles of cisplatin compared with 55.8% (34 patients) in 61 patients receiving two
cycles cisplatin. Consolidation therapy with fewer doses of cisplatin intake reduced toxicity.
In the Cox proportional-hazards model, baseline characteristics were considered in the
univariate Cox models. After accounting for the different cisplatin cycles among patients with
NPC, no significant risk factors were identified for either EFS or OS due to the limited sample size
in the three-cycle group (n=44) and lack of a sufficient number of incidents (5 out of 44). One
limitation of this thesis was the model's proportional hazards assumption. The investigation for
identifying if the Cox models meet the assumption was not performed.
17
From a long-term perspective, three cycles of cisplatin consolidation therapy in children
with NPC result in better performance, as the treatment may cause certain AEs. Because our
research focus was on children, we need to consider the probability of their long-term health. Our
future goal is to create attainable regimens that enhance cisplatin exposure and its radiation
synergistic impact (Denise et al., 2021). Moreover, we hope to develop the use of less toxic
therapies further. This is especially important in children and adolescents, in whom long-term
treatment can seriously affect the quality of life.
In conclusion, we have investigated the most current and relevant experiment of childhood
NPC, focusing on the comparison between this age cohort and adults. The study obtained the most
efficient evaluation of EFS and OS in three-cycle of cisplatin consolidation therapy, which were
both closed to 90% over a 5-year time interval (EFS: 90.8%, OS: 92.1%). Other advancements in
NPC treatment will necessitate the development of larger-scale clinical studies (Marie et al., 2018).
Still, the young population is in growth spurt period, we need to take this situation into
consideration when making a childhood NPC treatment plan.
18
References
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Iyad Sultan, Michela Casanova, Andrea Ferrari, Rawad Rihani, Carlos Rodriguez-Galindo. (2010,
August). Differential features of nasopharyngeal carcinoma in children and adults: a SEER
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Lawrence S. Young and Christopher W.Dawson. (2014). Epstein-Barr virus and nasopharyngeal
carcinoma. Chin J Cancer.
Carlos Rodriguez-Galindo, MD, Mark D. Krailo, PhD, Matthew J. Krasin, MD, Li Huang, MS, M.
Beth McCarville, MD, John Hicks, MS, DDS, MD, PhD, Farzana Pashankar, MD, and
Alberto S. Pappo, MD (2019). Treatment of Childhood Nasopharyngeal Carcinoma With
Induction Chemotherapy and Concurrent Chemoradiotherapy: Results of the Children’s
Oncology Group ARAR0331 Study. An American Society of Clinical Oncology Journal.
Daniel Ka Leung Cheuk, Catherine A Billups, Michael G Martin, Cynthia R Roland, Raul C
Ribeiro, Matthew J Krasin, Carlos Rodriguez-Galindo. (2010, August 24). Prognostic
factors and long-term outcomes of childhood nasopharyngeal carcinoma. Retrieved from
PubMed.gov: https://pubmed.ncbi.nlm.nih.gov/20737561/
Wei-Xiong Xia, Xing Lv, Hu Liang, Guo-Ying Liu, Rui Sun, Qi Zeng, Si-Wei Li, Hao-Yuan Mo,
Fei Han, Dong-Hua Luo, Qing Liu, Meng-Yun Shi, Yan-Fang Ye, Jing Yang, Liang-Ru Ke,
Meng-Yun Qiang, Wen-Ze Qiu, Ya-Hui Yu, Kui-Yuan Liu, Xin-Jun Huang, Wang-Zhong
Li, Shu-Hui Lv, Zhuo-Chen Cai, Jing-Jing Miao, Ling Guo, Ming-Yuan Chen, Ka-Jia Cao,
Lin Wang, Chong Zhao, Pei-Yu Huang, Qiu-Yan Chen, Yi-Jun Hua, Lin-Quan Tang, Chao-
Nan Qian, Hai-Qiang Mai, Xiang Guo and Yan-Qun Xiang. (2021). A Randomized
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Controlled Trial Comparing Two Different Schedules for Cisplatin Treatment in Patients
with Locoregionally Advanced Nasopharyngeal Cancer. AACR Journals, 4186-4193.
Carlos Rodriguez-Galindo, MD. (2013). Treatment of Childhood Nasopharyngeal Carcinoma with
Neoadjuvant Chemotherapy and Concomitant Chemoradiotherapy. Boston: Dana-Farber
Cancer Institute.
Vikas C. Raykar, Harald Steck, Balaji Krishnapuram, Cary Dehing-oberije, Philippe Lambin.
(2007). On Ranking in Survival Analysis: Bounds on the Concordance Index. umd.edu.
Denise Adams,Karen J. Marcus, William H. Meyer, Paul A. Meyers, Thomas A. Olson, Alberto S.
Pappo, Arthur Kim Ritchey, Carlos Rodriguez-Galindo, Stephen J. Shochat. (2021).
Childhood Nasopharyngeal Cancer Treatment (PDQ®)–Health Professional Version.
National Cancer Institute.
Marie-Emilie Dourthe , Stéphanie Bolle , Stéphane Temam , Anais Jouin , Line Claude , Yves
Reguerre , Anne-Sophie Defachelles , Daniel Orbach , Brice Fresneau. (2018). Childhood
Nasopharyngeal Carcinoma: State-of-the-Art, and Questions for the Future. Pubmed.gov.
Abstract (if available)
Abstract
Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCR) are the main effective treatments for childhood nasopharyngeal carcinoma (NPC). The incidence in children is rare in the United States. The Children’s Oncology Group ARAR0331 protocol was initially designed as three cycles of cisplatin during 6 weeks of radiation. However, the intolerant event led to a delay in chemotherapy that made three cycles of cisplatin impossible to administer within the 6–7-weeks radiotherapy. Therefore, the protocol was redesigned to only two cycles of cisplatin during radiotherapy. This study includes 105 Stratum B (stages IIb – IV) participants with NPC. The average age of the patients was 14 years old, and 48.57% were African American. The primary purpose of this thesis is to compare the efficacy and toxicity between two and three cycles of cisplatin consolidation therapy in patients with NPC enrolled in the American Joint Committee (AJCC) with stage IIb to stage IV cancer. Participants with NPC were evaluated for their tolerance to three cycles of cisplatin, and the study committee decided to omit one cycle of cisplatin due to the intolerability events. To investigate the efficacy of reduced cisplatin treatment during the consolidation therapy on survival outcomes, participants with three cycles of cisplatin in CCR (n = 44) or two cycles of cisplatin in CCR (n = 61) were divided into two groups. The Kaplan-Meier method was used to estimate the survival function, and the primary outcomes were event-free survival (EFS) and overall survival (OS). For the EFS events, the 5-year survival estimation for 81.0% (95% CI: 68.2%, 89.0%) for the two-cycle CCR treatment group, versus three-cycle CCR treatment was 90.8% (95% confidence interval [CI]: 77.3%, 96.4%, Hazard Ratio (HR)= 55.5%) (P= 0.268), the hazard ratio of 55.5% told us that the hazard rate in the for three-cycle CCR treatment group is 0.555 times of that in the two-cycle group. For the OS events, the 5-year survival estimation for two-cycle CCR treatment was 91.4% (95% CI: 80.6%, 96.3%), versus 92.1% (95% CI: 77.3%, 97.4%, HR= 71.1%) for the three-cycle CCR treatment group (P= 0.578), the hazard ratio of 71.1% told us that the hazard rate in the three-cycle CCR treatment group is 0.711 times of that in the two-cycle group. Toxicity analysis indicated that 34 patients (55.7%) experienced adverse events (AEs) classified as grades 3, 4 or both in the two-cycle group, and 41 patients (93.2%) experienced AEs in the three-cycle group. Total 75 out of 105 patients (71.4%) suffered from AEs, including 55.7% of patients who experienced an AE of grade 3 or higher toxicity in the two-cycle cohort compared to 93.2% of patients who experienced AEs in three-cycle cohort. This study showed a decreased tendency of EFS for the patients who were given fewer cisplatin doses during CCR. In the meanwhile, patients in the three-cycle cisplatin group compared to two-cycle cisplatin group had a more frequent occurrence of AEs.
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Hao, Amei
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Comparison for efficacy and toxicity in 2 vs 3 cycles of cisplatin consolidation therapy in children nasopharyngeal carcinoma
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Keck School of Medicine
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Master of Science
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Biostatistics
Degree Conferral Date
2021-12
Publication Date
10/09/2021
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