Received: 13 December 2016 Revised: 10 April 2018 Accepted: 28 May 2018

DOI: 10.1002/hed.25379

CLINICAL REVIEW

Concurrent chemoradiotherapy with weekly versus triweekly

cisplatin in locally advanced squamous cell carcinoma of the head
and neck: A comparative analysis
Amr Mohamed MD1 | Brandon Twardy MD, PhD1 | Magdi A. Zordok MD2 | Khuram Ashraf MD7 |
Ayman Alkhoder MD2 | Kelly Schrapp MD7 | Conor Steuer MD3 | Zhengjia Chen PhD4 |
Suchita Pakkala MD3 | Rathi Pillai MD3 | J Trad Wadsworth MD5 | Kristin Higgins MD5 |
Jonathan J. Beitler MD5 | Suresh S. Ramalingam MD3 | Taofeek K. Owonikoko MD, PhD3 |
Fadlo R. Khuri MD3 | Dong M. Shin MD3 | Madhusmita Behera PhD6 | Nabil F. Saba MD3

1
Department of Medical Oncology, Karmanos
Cancer Institute, Wayne State University, Detroit, Abstract
Michigan Background: Cisplatin-based chemoradiotherapy is standard of care for locally
2
Department of Medicine, Emory University, advanced squamous cell carcinoma of the head and neck. This systemic review
Atlanta, Georgia
compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced
3
Department of Hematology and Medical
squamous cell carcinoma of the head and neck.
Oncology, Emory University, Atlanta, Georgia
4
Methods: Among 1500 prospective studies published from 1970 to 2015,
Department of Biostatistics and Bioinformatics,
Emory University, Atlanta, Georgia 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clini-
5
Department of Radiation Oncology, Emory cal outcomes were analyzed using weighted estimates and 2-tailed t test for com-
University, Atlanta, Georgia parisons; significance level was 0.05.
6
Winship Cancer Center of Emory University, Results: Locoregional control was 58% (CI 53%-63%) vs 61% (CI 56%-65%;
Atlanta, Georgia P = .7). The 2-year overall survival (OS) was 74% (CI 66%-80%) for weekly vs 67%
7
Department of Medicine, Morehouse School of (64%-69%) triweekly groups (P = .67). The 2-year progression-free survival (PFS)
Medicine, Atlanta, Georgia
was 69% (CI 59%-77%) for weekly vs 62% (CI 58%-65%) triweekly groups (P = .9).
Correspondence
Nabil F. Saba, Professor, Department of
Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups.
Hematology and Medical Oncology, Director of Conclusions: Weekly cisplatin was comparable in efficacy and safety to the tri-
the Head and Neck Medical Oncology Program, weekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in
Emory University, Atlanta, GA.
Email: nfsaba@emory.edu
locally advanced squamous cell carcinoma of the head and neck, with tolerability
being a key factor in selection.

KEYWORDS

cisplatin and radiotherapy in head and neck cancer, concurrent therapy,

concurrent therapy in squamous cell carcinoma of the head and neck, weekly
cisplatin, weekly cisplatin in head and neck cancer

1 | INTRODUCTION of the upper aerodigestive tract. Squamous cell carcinoma

Squamous cell carcinomas of the head and neck can arise in
several anatomic locations, mostly in the mucosal surfaces
The abstract for this manuscript was accepted and received the Merit award
for the ASCO 2015 annual meeting.
of the head and neck accounts for more than 550 000 cases
worldwide each year.1,2 In the United States, squamous cell
carcinoma of the head and neck accounts for 3% of all can-
cers, with almost 60 000 new cases and 12 000 deaths
annually.3 The majority of patients with squamous cell car-
cinoma of the head and neck present with advanced disease

Head & Neck. 2019;1–9. wileyonlinelibrary.com/journal/hed © 2019 Wiley Periodicals, Inc. 1

2 MOHAMED ET AL.

and local control is a primary measure of success.4 Over the

past decade, several trials have focused on improving locor-
egional control (LRC) and disease-free survival in patients
with locally advanced disease. Most concurrent modality
trials that used cisplatin- based chemoradiotherapy
improved long-term survival and LRC when compared with
radiotherapy alone.5 Various schedules of cisplatin have
been used with the intent to improve compliance and toxic-
ity. Among these regimens, the most widely used is the tri-
weekly regimen of cisplatin 100 mg/m2 concurrently with
radiotherapy. There has been a recent increase in the use of
the weekly cisplatin regimen with doses ranging from 30 to
40 mg/m2 in an attempt to prevent the triweekly side
effects. Several previous randomized trials and meta-
analyses have investigated the efficacy of the triweekly regi-
men.6,7 For example, the MACH meta-analysis pooled data
from trials performed between 1965 and 1993 including
10 741 patients, and showed an absolute 5-year survival
advantage of 4% with the addition of cisplatin in the concur-
rent setting.8 Despite the improvement in outcome, toxicity
was significant and included nephrotoxicity as well as grade
3/4 mucositis, leukopenia, and myelosuppression.9,10 This
prompted the exploration of the weekly regimen, which has
recently been incorporated into major cooperative group
clinical trials such as the Radiation Therapy Oncology
Group RTOG1216 and NRG HN 002. In the midst of all
FIGURE 1 Consort diagram outlining the study selection [Color figure this, there continues to be a lack of randomized trials com-
can be viewed at wileyonlinelibrary.com] paring the 2 approaches.11 Despite clear evidence that

TABLE 1 Study characteristics in weekly cisplatin

No. of patients No. of patients

Cisplatin Median with with
treatment No. of age Sex classification classification
Study Phase design (S/D) RT patients (years) (male/female) III disease IV disease
Beckmann GK et al15 II Weekly 160 mg/m2 69.9 Gy 37 59 32/5 2 35
16 2
Sarkar SK et al Single (randomized) Weekly 240 mg/m 66 Gy 40 55 32/8 23 17
Jain RK et. al5 Single (randomized) Weekly 180 mg/m2 70 Gy 45 56 35/10 25 20
Essa HH et al17 Single (randomized) Weekly 180 mg/m2 70 Gy 20 55.7 18/2 5 15
Maguire PD et al18 II Weekly 180 mg/m2 70 Gy 39 57 32/7 15 24
19 2
Loimu V et al Single Weekly 240 mg/m 70 Gy 83 58 69/14 70 5
Quon H20 III (randomized) Weekly 140 mg/m2 70 Gy 149 61 117/32 21 128
Pala et al21 Single Weekly 200 mg/m2 70 Gy 148 56 127/21 30 118
Majumder D et al22 Single (randomized) Weekly 180 mg/m2 66 Gy 21 63 17/4 13 8
Gómez-Millán J et al23 II Weekly 160 mg/m2 72 Gy 43 58 43/0 9 34
24
Dimri K et al Single Weekly 180 mg/m2 66 Gy 188 50 168/20 114 78
Kataria T et al25 Single (randomized) Weekly 200 mg/m2 70 Gy 32 74 27/5 9 18
Kumar S et al26 II Weekly 210 mg/m2 70 Gy 95 55.2 83/12 31 64
27 2
Medina JA et al II Weekly 160 mg/m 72 Gy 94 58 86/8 19 75
Sharma A et al28 III (randomized) Weekly 240 mg/m2 70 Gy 77 50 71/6 29 43
Mostafa M et al29 Single (randomized) Weekly 180 mg/m2 70 Gy 30 47.9 NA NA NA
Bhatnagar A et al30 Single (randomized) Weekly 210 mg/m2 70 Gy 25 NA NA NA NA
Uygun K et al6 Single Weekly 300 mg/m2 70 Gy 20 71 15/5 4 16

Abbreviations: CT, cisplatin treatment; RT, radiotherapy; S/D, schedule/dose.

MOHAMED ET AL. 3

TABLE 2 Study characteristics in triweekly cisplatin

No. of patients No of patients

Cisplatin Median with with
treatment No. of age Sex classification classification
Study Phase design (S/D) RT patients (years) (male/female) III disease IV disease
Al-Sarraf M et al31 Single Triweekly 300 mg/m2 70 Gy 124 58 96/28 22 102
32
Gasparini G et al Single Triweekly 240 mg/m2 70 Gy 32 NA NA NA NA
Fountzilas G et al33 Single Triweekly 300 mg/m2 70 Gy 48 55 42/6 42 0
9
Adelstein D et al III (randomized) Triweekly 300 mg/m2 70 Gy 87 56.8 76/11 20 67
34 2
Forastiere et al Single (randomized) Triweekly 300 mg/m 70 Gy 172 60 137/35 115 57
Fountzilas G et al35 III (randomized) Triweekly 300 mg/m2 70 Gy 45 57 41/4 7 38
Ang K et al36 II Triweekly 200 mg/m2 72 Gy 76 57 60/16 9 67
37
De Castro G et al Single Triweekly 300 mg/m2 70 Gy 30 53 25/5 0 30
38 2
Garden AS et al II Triweekly 200 mg/m 72 Gy 76 57 60/16 9 67
Uygun K et al6 Single Triweekly 300 mg/m2 70 Gy 30 53.2 24/6 9 21
Kiprian D et al39 Single Triweekly 300 mg/m2 67 Gy 99 55 74/25 44 22
Rishi A et al40 III (randomized) Triweekly 300 mg/m2 66 Gy 106 49 101/5 50 56
41 2
Martins et al II (randomized) Triweekly 300 mg/m 70 Gy 105 NA 84/20 38 27
Ang K et al42 III (randomized) Triweekly 200 mg/m2 70 Gy 447 57 387/60 59 388
Mesia R et al43 II (randomized) Triweekly 300 mg/m2 70 Gy 63 NA 57/6 15 48
Hayes D et al44 II (randomized) Triweekly 300 mg/m2 70 Gy 128 55.7 111/17 NA NA
45 2
Giralt J et al II (randomized) Triweekly 300 mg/m 70 Gy 63 57 55/8 NA NA
Ang K et al46 III (randomized) Triweekly 300 mg/m2 70 Gy 231 NA NA NA NA
Marcial VA et al47 Single Triweekly 300 mg/m2 73 Gy 124 58 96/28 22 102
48
Rodriguez CP et al III (randomized) Triweekly 260 mg/m2 70 Gy 35 60 32/3 NA NA
Nguyen-tan PF et al49 III (randomized) Triweekly 300 mg/m2 70 Gy 361 56 309/52 4 31

Abbreviations: CT, cisplatin treatment; RT, radiotherapy; S/D, schedule/dose.

FIGURE 2 Locoregional control (LRC) in weekly versus triweekly cisplatin groups [Color figure can be viewed at wileyonlinelibrary.com]
4 MOHAMED ET AL.

TABLE 3 Clinical outcome in weekly versus triweekly cisplatin included (Cisplatin AND Weekly OR Tri-weekly AND head
Clinical outcome Weekly cisplatin Triweekly cisplatin P value and neck cancers) with the filters “clinical trial” and
LRC 58% (CI 53%-63%) 61% (CI 56%-65%) 0.7 “humans.” Authors who took part in the meta-analysis were
ORR 89% (CI 77%-95%) 72% (CI 51%-86%) 0.14 also asked to identify and review the included trials.
Survival
2 years 74% (CI 66%-80%) 67% (64%-69%) 0.67
5 years 48% (CI 42%-53%) 51% (CI 47%-54%) 0.6
3 | E LI G IB IL IT Y C RI TER I A
PFS
Trials were independently reviewed by three of the authors
2 years 69% (CI 59%-77%) 62% (CI 58%-65%) 0.9
for eligibility criteria. A trial was deemed eligible if it was a
Abbreviations: LRC: locoregional control; ORR: overall response rate; OS: over- randomized phase II or III trial with results published
all survival; PFS: progression-free survival.
between 1970 and 2015. Trials included previously
effectiveness is affected by the total cumulative cisplatin untreated patients with localized advanced SCCHN that had
dose rather than schedule,12 no clear schedule has been uni- undergone a potentially curative locoregional treatment and
formly adopted.13,14 We sought to conduct this comparative had not been treated for another cancer. Trials including
analysis of published trials of weekly vs triweekly cisplatin patients with oral cavity, oropharynx, hypopharynx, and lar-
regimens to explore possible differences in efficacy and ynx were included. Trials including patients with only naso-
safety. Our hypothesis was that the weekly cisplatin regi- pharyngeal carcinomas or those that enrolled fewer than
men is as efficacious as the triweekly regimen with no 10 patients were excluded. Trials used either weekly or tri-
increased toxicity. weekly cisplatin, in combination with radiotherapy. A total
cisplatin dose of at least 180 mg/m2 was required; a radia-
tion dose of at least 60 Gy was required. Studies were
2 | IDENTIFICATION OF TRIALS excluded if induction therapy was part of the regimen, or if
5-fluorouracil (5-FU) or other targeted agents were used.
Computerized search of MEDLINE, Embase, and relevant Postoperative, adjuvant, intraarterial, or oral cisplatin trials
abstracts from the annual meeting of American Society of were excluded. Institutional approval and informed consent
Clinical Oncology and American Association of Cancer were not required for this study because it was a systematic
Research was conducted. Search terms that were used review of previously conducted studies.

FIGURE 3 Objective response rate (ORR) in weekly versus triweekly cisplatin groups [Color figure can be viewed at wileyonlinelibrary.com]
MOHAMED ET AL.
FIGURE 4 A, The 2-year overall survival (OS) in weekly versus triweekly cisplatin groups. B, The 5-year OS in weekly versus triweekly cisplatin groups
[Color figure can be viewed at wileyonlinelibrary.com]
4 | DA T A E XT RA CT IO N A N D
S T A T I S T I C AL A NA L Y S I S
The data collected from each study included date of
randomization, phase of study, median age, sex, tumor
site, classification, treatment regimen (weekly, tri-
weekly, or both), total dose of cisplatin and radiother-
apy, as well as all reported grade 3 to 5 toxicities.
Treatment and clinical outcomes included objective
5
response rate (ORR), LRC at 2 years and 5 years,
2-year and 5-year OS rates, 2-year PFS, and any avail-
able toxicity data. All data were checked for internal
consistency and compared with the trial's protocol and
published reports. In our included trials, the response
evaluation was performed 4 to 6 weeks after the end of
concurrent chemoradiotherapy and relied on CT and/or
MRI, and in some trials on endoscopic evaluation and
biopsy to investigate residual disease. The weighted
6 MOHAMED ET AL.
FIGURE 5 The 2-year progression-free survival (PFS) in weekly versus triweekly cisplatin groups [Color figure can be viewed at wileyonlinelibrary.com]
mean of the OS was compared for the 2 groups from
those studies that reported the data. The weighted mean
PFS time was compared for the 2 groups from those
studies that reported the data.
5 | AN AL YSIS
Trials were grouped according to the schedule of chemora-
diotherapy (weekly vs triweekly). All analyses were con-
ducted on an intent-to-treat basis. Median follow-up was
computed by the potential follow-up method. Analysis for
LRC, OS, and PFS was stratified by trial, and its variance
was used to calculate individual and overall pooled hazard
ratios with a random and fixed-effect model. The absolute
differences at 2 and 5 years were calculated with the baseline
event rate in the 2 arms. All analyses were performed using
Comprehensive Meta-Analysis software (CMA version 2.0)
and SAS statistical package V9.3 (SAS Institute, Cary, NC,
United States). The differences in outcomes are presented as
pooled proportions and demonstrated as forest plots.
Through search by title and abstract in about 1500 trials
using the search strategy (Cisplatin weekly AND Tri-weekly
AND head and neck cancers), 100 studies were identified.
Sixty-one trials were excluded. A total of 39 studies
(18 weekly, 21 triweekly) with 3668 patients qualified for
inclusion and were retrieved (Figure 1). The number of
patients treated with weekly cisplatin was 1186 (81% men),
and triweekly was 2482 (75% men). Median age was 57.9
and 56.1 years for weekly and triweekly therapy, respec-
tively. The median cisplatin doses were 200 and 300 mg/m2
for weekly and triweekly therapy, respectively. Both groups
received a median dose of radiotherapy of 70 Gy. Classifica-
tion IV disease was identified in 57% for weekly and 69% for
triweekly groups. Median follow-up for the weekly group was
37 months vs 41 months for the triweekly group. Treatment
outcomes (LRC, OS, and PFS) were available in 36 of 39 stud-
ies, and a toxicity profile was available in 37 of 39 studies. In
38 of 39 studies, imaging using either CT/MRI or endoscopic
evaluation was performed to assess response rate. Details of
the selected studies are provided in Tables 1 and 2.
6 | L O CO RE GI O NA L C ON T R OL
Our analysis did not show a difference in the rate of LRC
between the weekly and triweekly groups. The weighted
pooled overall LRC for patients treated with weekly cisplatin
(N = 511) was 58% (CI 53%-63%) vs (N = 611) 61%
(CI 56%-65%), for those treated with triweekly cisplatin
(p value = .7). There was no statistically significant differ-
ence in the distant failure between the weekly cisplatin
11.4% (N = 39/342) and triweekly 12.04% (N = 39/324),
(95% CI -4.27%-5.61%), (p value 0.7975) regimens. The
summary estimate of LCR of the weekly group or triweekly
group was calculated by combining the LCR of each trial in
the group through weighting their log (base) LCRs by the
inverse of their variances (Figure 2).
TABLE 4 Grade 3 to 5 toxicity profile in weekly versus triweekly cisplatin
Toxicity profile Weekly cisplatin Triweekly cisplatin P value
Grade 3-5 toxicities 36% (CI 31%-41%) 40% (CI 37%-43%) 0.37
Grade 3-5 mucositis 35% (CI 27%-44%) 36% (CI 28%- 44%) 0.73
MOHAMED ET AL. 7

7 | OB J E C T I VE R E S P ON S E R AT E (CI 58%-65%) for the triweekly group (P = .9). The

weighted pooled 2-year PFS rates for patients treated with
The weighted pooled overall ORR for patients treated with weekly cisplatin vs triweekly cisplatin are shown in Table 3
weekly cisplatin (N = 648) was 89% (CI 77%-95%), and and Figure 5.
(N = 544) 72% (CI 51%-86%) for those treated with tri-
weekly cisplatin. Even though the ORR for the weekly
group was higher compared to triweekly group, the results 1 0 | T OX I C I T I E S
were not statically significant (P = .14) (Table 3) (Figure 3).
Grade 3 to 5 hematologic, intestinal, neurologic, and renal
toxicities (N = 569 patients in weekly vs 1463 in triweekly)
8 | OV E R AL L S U RV IV AL
were similar between the 2 groups:36% (CI 31%-41%) vs
40% (CI 37%-43%) for weekly and triweekly, respectively;
The 2-year (N = 172 patients in weekly vs 1300 in triweekly)
P = .37; Table 3. In addition, Grade 3 to 5 mucositis was
and 5-year (N = 314 patients in weekly vs 809 in triweekly)
similar for the 2 groups (P = .73). Mucositis and dysphagia
survival were estimated to be statistically similar, 74%
were reported to be the most common adverse events in both
(CI 66%-80%) and 48% (CI 42%-53%) for weekly vs 67%
groups. The weighted pooled grade 3 to 5 toxicities for
(64%-69%) and 51% (CI 47%-54%) for triweekly (P = .67 and
patients treated with weekly cisplatin vs triweekly cisplatin
P = .6), respectively. The weighted pooled median, 2-year,
are shown in Table 4 and Figure 6.
and 5-year OR for patients treated with weekly cisplatin vs tri-
weekly cisplatin are shown in Table 3 and Figure 4(a)(b).
11 | DISCUSSION
9 | P R OG R E S S I O N- F R E E S U RV IV A L
Concurrent cisplatin and radiotherapy remains the standard
The 2-year PFS (N = 140 patients in weekly vs 963 in tri- of care in squamous cell carcinoma of the head and neck.
weekly) was 69% (CI 59%-77%) for the weekly vs 62% Cisplatin has improved the clinical outcome for patients,

FIGURE 6 Toxicity profile in weekly versus triweekly cisplatin groups [Color figure can be viewed at wileyonlinelibrary.com]
8 MOHAMED ET AL.
however at a price of increased toxicity. We report the larg-
est comparative analysis between the weekly vs triweekly
cisplatin regimens. We have tried to control for variables
that could have influenced the results such as total dose of
cisplatin, sequencing of therapy, dose of radiotherapy, as
well as size of reported studies. Our results have failed to
show a clear difference in the rate of LRC, OS, or response
rates between the 2 cisplatin regimens; this analysis there-
fore does not support the use of one vs the other and falls
short of providing a clear answer as to the regimen of
choice. The use of weekly cisplatin has gained momentum
over the last years and is being adopted as an alternative to
the presumably more toxic triweekly regimen.53 It is of
note, however, that until clear toxicity data are available, it
is hard to reach a conclusion as far as one regimen of
choice based on our analysis; we have found, however, no
clear toxicity disadvantage to the weekly or triweekly
regimen.
The fact that no considerable difference was detected as
far as PFS and OS at 2 and 5 years suggests a lack of inferi-
ority of the weekly regimen.
The observed trend in PFS in favor of the triweekly regi-
men was not statistically significant and can be possibly
attributed to the higher number of study patients in the tri-
weekly compared to the weekly arm.
Of note are recent reports using the LORHAN data
favoring a significant difference in OS favoring the tri-
weekly group53; this analysis was, however, limited by
incomplete follow-up data (>75% censored in both
cohorts). Other limitations include the significantly differ-
ent baseline characteristics of the 2 groups with patients
receiving the weekly regimen being older, with low perfor-
mance status, and more likely to be smokers and having a
lower socioeconomic status. Despite the fact that our analy-
sis could not control for these factors, these would have
favored the triweekly group. Because the cumulative dose
of cisplatin does seem to affect the overall outcome we
have attempted to control for the total cisplatin dose in our
selection of trials.54
Despite the lack of clear toxicity difference in our analy-
sis one could make the argument that the frequent monitor-
ing of toxicities with laboratory values and clinic visits may
put the weekly cohort at an advantage; however, this
remains an unproven possibility.
Significant limitations exist in this and similar compara-
tive analyses: it was conducted using published randomized
controlled trials with no available individualized patient
data; it included trials with heterogeneous study models,
diverse patient populations, and different follow-up periods.
In addition, there was variation in the number of collected
studies documenting OS and PFS in the 2 arms. Despite this
heterogeneity, we think, howeve, that the stringent inclusion
criteria helped to quell some of these concerns. We hope this
analysis will assist in guiding clinical decisions as far as
schedule of cisplatin in the concurrent setting; however, it
clearly cannot be used as a practice shifting evidence.
CONFLICT OF IN TER EST
None of the authors has a conflict of interest to declare.
OR CID
Dong M. Shin https://orcid.org/0000-0002-8245-4174
Nabil F. Saba https://orcid.org/0000-0003-4972-1477
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SUPPORTING I NFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
How to cite this article: Mohamed A, Twardy B,
Zordok MA, et al. Concurrent chemoradiotherapy
with weekly versus triweekly cisplatin in locally
advanced squamous cell carcinoma of the head and
neck: A comparative analysis. Head & Neck. 2019;
1–9. https://doi.org/10.1002/hed.25379