THIEME

Original Research

Primary Concurrent Chemoradiation in Head and

Neck Cancers with Weekly Cisplatin Chemotherapy:
Analysis of Compliance, Toxicity and Survival
Muhammad Shahid Iqbal1 Cheng Chaw2 Josef Kovarik1 Shahzeena Aslam3 Aaron Jackson4
John Kelly1 Werner Dobrowsky1 Charles Kelly1

1 Department of Clinical Oncology, Northern Centre for Cancer Care, Address for correspondence Muhammad Shahid Iqbal, FRCR,
Newcastle upon Tyne, United Kingdom of Great Britain and Northern Department of Clinical Oncology, Northern Centre for Cancer Care,
Ireland Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom of
2 Department of Clinical Oncology, Ninewells Hospital, Dundee, Great Britain and Northern, Ireland (e-mail: [email protected]).
Dundee, United Kingdom of Great Britain and Northern Ireland
3 Department of Clinical Oncology, Clinical Oncology, Addenbrookes
Hospital, Cambridge, Cambridgeshire, United Kingdom of Great
Britain and Northern Ireland
4 Department of Research, Northern Centre for Cancer Care,
Newcastle upon Tyne, United Kingdom of Great Britain and Northern
Ireland

Int Arch Otorhinolaryngol

Abstract Introduction Concurrent chemoradiation is the standard of care in inoperable locally

advanced squamous cell head and neck cancers. The most widely accepted schedule of
concomitant cisplatin is 100mg/m2 given on a 3 weekly basis but the optimal regime is
unknown.
Objective The objective of this study is to assess the tolerability, compliance, and
clinical outcomes of weekly cisplatin (40mg/m2).
Methods During the period of January 2007–December 2009, we analyzed retrospec-
tively 122 patients with histologically proven squamous cell carcinoma of head and neck
(nasopharynx, oropharynx, larynx, hypopharynx, and oral cavity) treated with definitive
chemoradiation. All patients received 63 Gy in 30 daily fractions with concomitant
weekly cisplatin 40mg/m2. We assessed treatment toxicities and patient compliance.
We estimated overall survival using the Kaplan-Meier method.
Results Sixty-eight percent of patients managed to complete all six cycles of chemother-
apy while 87% of patients completed at least 5 cycles of weekly cisplatin. Incidence of grade
3/4 toxicity was as follows: mucositis 33%, dermatitis 41%, dysphagia 15%, mouth/neck pain
17%, neutropenia 2%, and renal impairment 3%. 53% patients required at least one hospital
admission for symptom control. The 5-year overall survival rate was 60%.
Keywords Conclusion Concurrent chemoradiotherapy using weekly cisplatin at 40mg/m2 per
► head and neck week is an effective, well tolerated regimen allowing most patients to receive at least 5
neoplasms cycles of chemotherapy. However, a phase III randomized control trial comparing the
► chemoradiotherapy standard dose of 100mg/m2 cisplatin tri-weekly with a weekly regimen is needed to
► cisplatin establish the long term clinical outcome.

received DOI http://dx.doi.org/ Copyright © by Thieme Publicações Ltda,

April 11, 2016 10.1055/s-0036-1594020. Rio de Janeiro, Brazil
accepted ISSN 1809-9777.
September 9, 2016
Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy Iqbal et al.

Introduction with Objectives with T2N2 oropharyngeal carcinoma, received cetuximab. He

remained alive after five years of follow-up. The remaining three
Head and neck cancers (HNC) are heterogeneous group of patients received carboplatin. Of these three patients, two
cancers and as a whole, they are the fifth most common presented with stage IV disease with mixed histology of squa-
cancer worldwide with an estimated annual global incidence mous and small cell carcinoma. Both patients died after 4 and 6
of over half a million.1 Treatment approaches vary depending months of diagnosis. Third patient with stage III nasopharyngeal
upon the location of the tumor, staging, and individual carcinoma was lost to follow-up.
patient’s characteristics. Optimal treatment for locally The clinical characteristics of the patients are summarized
advanced HNC remains a challenge and concurrent chemo- in ►Table 1. The median age was 57 years (range: 35–79). The
radiotherapy is the established standard of care for patients majority of the patients had locally advanced disease (72%
with inoperable disease or patients in whom surgery would patients with stage IVa disease followed by 22% patients with
be associated with unacceptable morbidity. The main treat- stage III disease, ►Table 2). A significant number of patients
ment modality is external beam radiotherapy with or without (82%) had WHO performance status, 0 or 1. Seventy-nine
chemotherapy. The most commonly used chemotherapeutic patients were smokers or past smokers which represented
agent is cisplatin. The additional absolute benefit in overall 65% of the entire group.
survival of adding platinum based chemotherapy has been
best estimated as 6.5% at 5 years when compared with Pre-treatment Evaluation
radiotherapy alone.2 The optimal regimen of cisplatin is yet All patients underwent clinical evaluations by the otolaryngo-
to be defined. However, the most widely used concurrent logic-surgical team. Pre-treatment investigations included
chemoradiation schedule uses high-dose bolus cisplatin clinical history and examination, biopsies, imaging (CT  MRI
100mg/m2 every three weeks, in combination with standard and/or CT/PET scan), fitness evaluation with WHO perfor-
radiotherapy.3–6 The addition of concurrent chemotherapy to mance status, and ACE-27 (Adult comorbidity evaluation).7 A
high dose external beam radiotherapy is often associated multidisciplinary team comprising of otolaryngologists, clini-
with increased toxicity and affects patient compliance with cal oncologists, radiologists, pathologist, dental and plastic
treatment completion. It also often involves an in-patient stay surgeons, clinical nurse specialists, dieticians, and speech and
in the hospital for chemotherapy, which could potentially language therapists met and discussed all patients. The treat-
result in treatment delays. ment decisions were tailored individually based on clinical
Weekly cisplatin 40 mg/m2 has been the standard regimen staging, comorbidities, long term functional outcome, and
for concurrent chemoradiotherapy for HNC at our institution. patient’s choice.
This retrospective study attempts to review the experience of
external beam radiotherapy (63 Gy in 30 daily fractions) Chemotherapy
with concurrent weekly cisplatin 40 mg/m2. The objective of We administered weekly intravenous cisplatin in outpatient
this retrospective study was to review the efficacy of this day case settings with a dose of 40 mg/m2. We capped the
regime, evaluating the treatment response, patient compli- maximum dose at 70 mg. Patients received a pre- and post-
ance, toxicities, and outcomes of the treatment. We have also hydration of 1000 mL of sodium chloride 0.9%. Ten mmol of
investigated the prognostic factors affecting the clinical magnesium sulfate and 20 mmol of potassium chloride were
outcome. added in the post-hydration saline. Standard prophylactic anti-
emetic protocol was a combination of 5-hydroxytryptamine-3
(5HT3) – antagonists (ondansetron) and dexamethasone.
Methods
Patient Population Radiotherapy Schedule
Patients with head and neck cancers who underwent definitive All patients were treated in a supine position, immobilized
primary chemoradiotherapy over a period of three years (Janu- with a customized 5-point beam directed shell. The target
ary 2007–December 2009) were identified from our department volume definition was performed using Oncentra MasterPlan
database. We only included patients with a histologically proven (Nucletron B.V. Veenedaal, Netherlands) Treatment Planning
squamous cell carcinoma of the nasopharynx (n ¼ 7), orophar- System, and the radiation treatment was delivered using step
ynx (n ¼ 74), larynx (n ¼ 12), hypopharynx (n ¼ 16) and oral and shoot intensity modulated radiotherapy (IMRT). All
cavity (n ¼ 13). We excluded patients with primary tumors of patients received 63 Gy in 30 daily fractions over six weeks
salivary glands, nasal cavity, paranasal sinuses, and unknown to the primary tumor site and involved neck nodes. This was
primaries or patient with non-squamous cell carcinomas. We just post-transitional period of switching from 3D conformal
also excluded from the study patients treated adjuvantly or those radiotherapy to IMRT for head and neck cancers in our
who received chemotherapy other than weekly cisplatin. In total, department so the dose was kept at 63 Gy. However, later
there were 16 patients who received chemotherapy other than the dose was increased to 65 Gy in 30 fractions, which is our
weekly cisplatin. Out of these 16 patients, 12 (oropharynx, standard regime now. The uninvolved contralateral neck
n ¼ 5; hypopharynx, n ¼ 3; oral cavity, n ¼ 3, larynx, n ¼ 1) nodes that carried an occult metastatic risk greater than
received treatment with mitomycin C. Of these 12 patients, ten 15% received a prophylactic dose of 54 Gy in 30 fractions.
were with stage IV. Seven patients died. The median survival of Radiotherapy was delivered with 6-MV photons using linear
this cohort was 58 months. One patient, a 57-year-old man accelerators.

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 Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy Iqbal et al.

Table 1 Summary of the patients and their disease characteristics Table 1 (Continued)

n % n %
Total number of patients 122 – No 108 90
Male/Female 97/25 80/20 Yes 12 10
Median age (years with range) 57 (35 -79) – Survival (of total 122 patients)
Disease location Alive 73 60
Nasopharynx 7 6 Dead 49 40
Oropharynx 74 61 Abbreviations: n, total number of patients; ACE-27, Adult Comorbidity
Larynx 12 10 Evaluation-27 as per RTOG guidelines7; CR, complete response; RD,
residual disease.
Hypopharynx 16 13
Oral cavity 13 11
Stage
I 1 1
Toxicity Evaluation
II 6 5 We assessed all patients on treatment on a weekly basis in a
III 27 22 review clinic comprising clinical oncologists/specialist regis-
IV 88 72 trars, clinical nurse specialists, dietician, speech and language
therapists, and a dental hygienist. We assessed and graded
WHO performance status
the treatment toxicities according to the radiation therapy
0 70 57
oncology group (RTOG) and common toxicity criteria (CTCAE)
1 30 25 guidelines.7 We recorded performance status, mucosal reac-
2 19 16 tion, skin reaction, full blood count, urea and electrolytes, and
3 3 3 liver function tests. Patients were considered unfit for che-
motherapy in the case of deterioration of performance status,
ACE-27
deterioration of kidney function (GFR < 50mL/min), or blood
0 90 74 count (absolute neutrophil count < 1.5 and platelets < 100).
1 18 15 For patients who we found to be unfit for a cycle of chemo-
2 10 8 therapy we omitted that particular cycle altogether. No dose
reductions were planned.
3 4 3
Number of weekly cisplatin chemotherapy cycles completed Outcome Evaluation
6 83 68 Six weeks after completion of treatment, all patients were
5 23 19 assessed in a joint Head and Neck clinic with the otolaryn-
gology surgical team. We clinically assessed response (clinical
4 6 5
examination followed by laryngoscopy with fiber optic laryn-
3 7 6 goscope). Subsequent follow-up visits were scheduled on
2 3 3 three monthly basis for the first year, a 3 to 6 monthly basis
Treatment outcome for the second year and a 6-monthly thereafter for a total
period of five years. Radiological imaging (CT or PET/CT) and
Response assessable 120 98
biopsies were performed if patients were found to have any
CR 92 75
suspicion of recurrence.
RD (clinically suspicious) 28 23
Salvage surgery 18 15 Data Collection and Statistical Analysis
Pathological CR 11 61 We collected the data retrospectively and analyzed the results
(of 18 using SPSS version 21. Overall survival (OS) was defined as the
patients) time between the dates of tissue diagnosis to the dates of
Confirmed RD 7 39 death/last seen in clinic. Kaplan-Meier estimates were per-
(of 18 formed to calculate the OS. The compliance of the patients to
patients) chemotherapy treatments were measured in terms of num-
Local recurrences (out of 120 evaluable patients) bers of cycles completed. We reviewed hospital admission
No 97 81 rates during chemoradiation treatment and evaluated factors
that resulted in poor treatment compliance. Univariate anal-
Yes 23 19
ysis with log rank test was performed to study different
Distant metastases factors correlating to survival and a p < 0.05 was considered
(Continued) statistically significant.

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Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy Iqbal et al.

Table 2 Tumor, node, and metastases (TNM) staging and T stage of each subsite (n ¼ 122)

N0 N1 N2a N2b N2c N3

T1 1 4 3 6 1 1
T2 5 9 5 8 4 1
T3 10 6 2 6 6 2
T4 9 7 8 9 9 0
T stage Nasopharynx Oropharynx Larynx Hypopharynx Oral cavity
T1 0 15 0 1 0
T2 4 18 2 5 3
T3 1 18 7 4 2
T4 2 23 3 6 8

Results Table 3 Summary of toxicities

Clinical Outcome: Treatment Compliance and Acute Toxicity n %

Toxicities Mucositis
Of 122 total patients, all but two patients completed radiothera-
Grade 1/2 82 67
py. Of these two patients, one patient developed an acute
cerebrovascular event while on treatment and the second Grade 3 38 31
patient required a prolonged hospital admission due to pneu- Grade 4 2 2
monia. Two thirds (68%) of patients managed to complete all six Dermatitis
cycles of weekly cisplatin chemotherapy as shown in ►Table 1.
Grade 1/2 72 59
Overall, 87% of patients managed to receive at least 5 cycles, that
is, a cumulative dose of 200 mg/m2. The remaining 13% of Grade 3 46 38
patients received 2–4 cycles of weekly cisplatin. The incidence Grade 4 4 3
of grade 3 or 4 toxicities was as follows: mucositis (33%), Dysphagia
dermatitis (41%), dysphagia (15%), mouth/neck pain (17%),
Grade 1/2 104 85
neutropenia (2%), and renal impairment (3%). These patients
and details of their toxicities are outlined in ►Table 3. Forty- Grade 3 17 14
seven percent of patients did not require hospital admission Grade 4 1 1
during the course of treatment. Forty percent of patients Mouth/neck pain
required one hospital admission for the management of their
Grade 1/2 71 58
acute toxicities. The remaining 13% of patients required multiple
hospital admissions (Range 2–4). Grade 3 18 14
Grade 4 3 3
Clinical Outcome: Response to the Treatment Neutropenia
Response was assessable in 120 patients. Ninety-two patients
Grade 1/2 26 21
(75%) achieved a clinical complete response. There was a clinical
Grade 3 1 1
suspicion of residual disease in twenty-eight patients (23%) and,
in this group, 18 patients were deemed fit for salvage surgery Grade 4 1 1
(surgery on primary site and neck dissection in 8 patients and Renal impairment 3 3
neck dissection alone in 10 patients). Eleven patients had Number of times of hospital admissions
complete pathological response following surgery and, in the
None 57 47
remaining seven patients, residual disease was confirmed.
Once 49 40
Survival Twice 7 6
Seventy-three (60%) patients were alive at the time of analysis. Thrice 6 5
Thirty-one patients (26%) were found to have recurrent disease
Four times 2 2
and out of these 31 patients, 19 had developed loco-regional

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 Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy Iqbal et al.

Fig. 1 Overall survival of all patients in the study with mean survival of
59 months (95% CI 53 - 64), with 73 patients alive and 49 censored cases.
Fig. 3 Subgroup analysis of overall survival by different tumor sites.

recurrence, 8 patients had distant metastases, and 4 patients had

developed both local recurrence and distant metastases. Overall
and progression free survival rates are shown in ►Figs. 1 and 2, neck squamous cell carcinomas. Cisplatin is the most com-
respectively. mon chemotherapeutic agent used in combination with
The authors also investigated the prognostic factors that radiotherapy. The underlying mechanism of cisplatin induced
affected the survival of patients in this study. We found that radiosensitization include inhibition of the repair of poten-
the WHO performance status (p < 0.001), stage of disease tially lethal damage and sublethal damage, its ability to form
(p < 0.02), and tumor subsite (nasopharynx being the most DNA adducts and cell cycle arrest in G2 phase.8 The optimal
favorable and oral cavity disease with worst prognosis, regimen of concurrent cisplatin chemotherapy remains un-
p < 0.02, ►Figs. 3 and 4) impacted on survival. However, defined, although the most robust evidence is the use of
gender (p < 0.7), age (p < 0.55), and number of chemothera- 100mg/m2 cisplatin on a 3-weekly basis. However, this high
py cycles completed (p < 0.11) had no statistically significant dose cisplatin is associated with significant acute and late
impact on survival outcome. toxicities and the completion rate of the regime remains a
challenge.3,9–12 Due to significant toxicities and poor compli-
ance, there has been a trend toward the use of low dose
Discussion
Definitive concurrent chemoradiotherapy is considered stan-
dard of care for inoperable locoregionally advanced head and

Fig. 2 Progression-free survival at 5 years (74%), mean progression Fig. 4 Subgroup analysis of progression free survival by tumor
free survival of 66 months (95% CI 60–71). subsites.

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Primary Concurrent Chemoradiation in Head and Neck Cancers with Weekly Cisplatin Chemotherapy Iqbal et al.

weekly cisplatin concurrently with radiotherapy. There are no arms.28 In a recent study by Rivelli et al, the authors have
randomized trials to support to the use of low dose weekly extensively reviewed the incidence of late toxicities in head
cisplatin to date; published studies are limited to early phase and neck cancer patients treated with cisplatin based chemo-
studies and some small retrospective studies. There are radiation. Dysphagia (25%), xerostomia (40% with IMRT),
several published studies with alternative cisplatin regimens hypothyroidism (42%), ototoxicity (27%), and osteoradionec-
such as 5–7 mg/m2/day, 5 days a week during a 7 week course rosis (4%) were the most frequently reported late toxicities.
of fractionated radiotherapy,13–15 5 doses of 20 mg/m2 for 5 Old age, advanced T stage, larynx/hypopharynx primary, and
consecutive days,16 or 20 mg/m2 on 5 days of weeks 1 and 517 neck dissection after chemoradiotherapy were found to be
during weeks 1, 4, and 7 of radiotherapy. Similarly, some predictive of late toxities.29
studies evaluate the role of weekly cisplatin with the dose This current study is one of the largest from a European
ranging from 30–60 mg/m2 for 6–7 weeks.18–24 single center. Our findings support those by Gupta et al, the
In a prospective phase II trial by Sharma et al, weekly largest published single institutional study. Our study
cisplatin 40 mg/m2 for 7 doses chemoradiotherapy (n ¼ 77; showed similar chemotherapy compliance with better out-
primary sites of oropharynx and nasopharynx) was compared comes. According to our experience, weekly cisplatin is easier
against radical radiotherapy alone. Complete response was to manage than 3-weekly cisplatin because of closer moni-
observed in 80.5% patients in the chemoradiotherapy group toring and its increased flexibility allows for easier dose
against 67.1% in the radiotherapy alone group (p ¼ 0.04) adjustment or omission in response to patient morbidity.
however, this benefit was associated with frequent treatment Homma et al reached the same conclusion in their study of 53
interruptions (28.9% versus 9.3%; p ¼ 0.003) and hospitalisa- patients.12 In our study, 6 patients were with stage I/II, which
tion (40.8% versus 20%). The incidence of grade III and IV acute may explain good survival.
toxicity was 40% in the chemoradiotherapy group versus 20% We recognize the limitations of this study. First this is a
in the radiotherapy alone group (p ¼ 0.015).19 retrospective study of patients with squamous cell carcino-
Uygun et al studied two different regimes of cisplatin in a mas of five primary sites of the same region. Second human
retrospective analysis. They reviewed weekly 40 mg/m2 papilloma virus (HPV) status was not available for the
(n ¼ 20) and 3-weekly regimen (n ¼ 30) of cisplatin in two patients with oropharyngeal disease as it was not routine
different population groups and there was a statistically simi- practice in our institution at that time. Third, the chemother-
lar response rate and a similar adverse event profile.25 How- apy dose was capped at a maximum of 70mg which poten-
ever, in a retrospective study, Geeta et al reached a different tially may have resulted in under dosage of some patients
conclusion: 3-weekly cisplatin was less toxic than a weekly with increased body habitus. However, this capping of
regime 40 mg/m2, however, the number of patients in this cisplatin dose may explain relatively less grade  3 toxicities
group was small (n ¼ 32).26 In another indirect retrospective in our study compared with other studies with weekly
comparison, Ho et al compared weekly cisplatin 33–40 mg/m2 cisplatin, as discussed above.
(n ¼ 24) with 3-weekly cisplatin 80–100 mg/m2 (n ¼ 27) with
concurrent radical radiotherapy. More patients received a
Conclusion
higher cumulative dose of at least 240 mg/m2 in the weekly
arm as compared with the 3-weekly cisplatin (p ¼ 0.04). None In conclusion, our study demonstrated weekly (40mg/m2)
of the patients in 3-weekly arm were able to receive the full cisplatin given concurrently with radiotherapy to a total dose
three cycles 100 mg/m2 (maximum cumulative dose of 200 of 63 Gy in 30 daily fractions over a period of six weeks can be
mg/m2). Similarly, more delays (41% versus 29%) and omission safely administered with acceptable toxicity and without
of chemotherapy (17.4% versus 5.6%) occurred in the 3-weekly compromising efficacy. However, a phase III randomized
compared with the weekly regime, however, toxicity, radio- control trial comparing the standard dose of 100mg/m2
therapy overall treatment time and delays were similar cisplatin tri-weekly with a weekly regimen is needed to
between the two groups.27 establish the long term clinical outcome.
In one of the largest studies documenting single-center
experience of weekly cisplatin 30mg/m2 concurrently with
radiotherapy (n ¼ 264), Gupta et al found that with the regimen References
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