Keywords
head and neck cancer - platinum - drug
Introduction
Head and neck cancer accounts for >600,000 new cases per year, with >300,000 deaths
annually worldwide, indicating a poor prognosis.[1] Patients with recurrent or metastatic squamous cell carcinoma of the head and neck
(RM-SCCHN) have an especially poor prognosis, with a median survival of approximately
6 months if untreated. Many of the adverse events (AEs) of therapy for this disease
involve the immune system, and care by a multidisciplinary team is essential. Platinum-based
chemotherapy with cetuximab is first-line chemotherapy in RM-SCCHN.[2]
[3] A phase III trial showed that nivolumab treatment resulted in improved overall survival
(OS), progression-free survival (PFS), and response rate (RR) with improved quality
of life (QOL) compared with standard chemotherapy for platinum-refractory disease
(cetuximab, methotrexate, and docetaxel).[4]
[5]
[6]
In Japan, nivolumab was approved for treatment of platinum-refractory SCCHN in March
2017.
We conducted a retrospective study of the 16 patients treated in our institution.
Patient and Methods
We examined the cases of 16 patients (all male; mean age: 69 years, range: 48–75 years)
with RM-SCCHN, who were treated at our institution from April 2017 to January 2018.
Four, six, and six patients had an Eastern Cooperative Oncology Group (ECOG) performance
status of 0, 1, and 2, respectively. The primary lesions were oropharyngeal in four
patients, hypopharyngeal in eight patients, oral cavity in two, larynx in one, and
maxilla in one. All tumors were squamous cell carcinoma. All had a smoking history;
two were current smokers and 14 were former smokers. The Brinkman index of all 14
patients was >100.
Two patients had unresectable local lymph node involvement, two patients had local
recurrences, eight patients had distant metastases, and four patients had locoregional
spread plus distant metastases.
A total of 14 patients (87.5%) had undergone radiotherapy. Systemic chemotherapy included
one regimen in one patient, two regimens in five patients, and three regimens in 10
patients. All patients had received platinum chemotherapy between one and three times
and 15 patients had also received cetuximab. All experienced recurrence within 6 months.
Pretreatment evaluation consisted of complete history and physical examination, complete
blood counts, liver and renal function tests, chest X-rays, and electrocardiograms
(ECGs). All patients underwent a computed tomography (CT) scan and fiberoptic endoscopy
of the head and neck. Tumor staging was performed based on CT findings using the TNM
classification of the UICC 7th edition. Nivolumab monotherapy was administered at
a dose of 3 mg/kg every 2 weeks.
Chemotherapy-related toxicities were quantified using the National Cancer Institute
Common Toxicity Criteria (Version 4.0).
Follow-up time for each patient was calculated as the time from the start of treatment
to March 31, 2018. Tumor responses was assessed according to response evaluation criteria
in solid tumors (RECIST), version 1.1, every 6 weeks.
Survival curves were generated using the Kaplan–Meier method. Safety and efficacy
analysis was conducted on an intention-to-treat basis, defined as all patients who
received at least one dose of nivolumab. PFS was calculated from the date of first
administration of nivolumab to disease progression, subsequent changes in therapy
(for example, chemotherapy), or death, whichever came first.
OS was determined from the date of the first administration of chemotherapy to the
date of death or the last confirmed date of survival. Statistical data were generated
using a commercial software (SPSS statistics 21[R], SPSS, Inc., Chicago, Illinois,
United States).
Results
Patient characteristics are summarized in [Table 1].
Table 1
Characteristics of the 16 patients
|
Characteristics
|
n
|
|
Age (y)
|
|
Median
|
69
|
|
Range
|
48–75
|
|
Sex
|
|
Male
|
16
|
|
Female
|
0
|
|
ECOG performance score
|
|
0
|
4
|
|
1
|
6
|
|
2
|
6
|
|
Site of primary tumor
|
|
Oropharynx
|
4
|
|
Hypopharynx
|
2
|
|
Oral cavity
|
2
|
|
Larynx
|
1
|
|
Other
|
1
|
|
No. of previous lines of systemic cancer therapy
|
|
1
|
1
|
|
2
|
5
|
|
≥3
|
10
|
|
Context of previous systemic therapy regimen no.
|
|
Primary disease
|
4
|
|
Metastatic disease
|
8
|
|
Primary + metastatic
|
4
|
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
The median number of infusions administered was 5 (range: 2–11). Of the 16 patients,
13 patients needed to discontinue nivolumab because of progressive disease in 10 patients
and Grade 3 AEs in three patients, including Grade 3 pneumonitis in one patient and
Grade 3 rash in two patients. These AEs were unresponsive to intravenous steroids,
and their clinicians requested the discontinuation of nivolumab therapy.
After discontinuation of nivolumab, 5 of 13 patients received further chemotherapy,
one with paclitaxel and cetuximab and four patients with S-1.
Efficacy
The median follow-up time was 8.3 months (range: 0.6–9.4 months). The median PFS was
2.1 months (95% confidence interval [CI]: 1.6–4.9) . The median OS was 8.7 months
(95% CI: 8.1–9.4). The PFS at 6 months was 14%. OS in patients with PD-L1 ≥ 1% was
3.8 months versus 6.7 months in those with PD-L1 < 1%.
The RR among nivolumab-treated patients was 12.0%, including two partial responses
by RECIST. The disease control rate was 81.2%. Time to onset of pneumonitis ranged
from 1 to 7 cycles (mean: 3.5 cycles), and time to onset of rash ranged from 2 to
6 courses (mean: 3.1 courses). No patients developed bacterial or viral pneumonia.
PD-L1 Expression and p16 Status
Tumor PD-L1 expression status and p16 status could be evaluated in 15 of 16 patients
(93.7%). Among these patients, 7 of 15 (43.7%) had a PD-L1 expression level of ≥ 1%.
Four of 15 patients were p16-positive.
Safety
The most common treatment-related AEs are shown in [Table 2].
Table 2
Treatment-related adverse events in the patients (all were Grade 1–3)
|
All grades, n (%)
|
Grade 3, n (%)
|
|
Any event
|
11 (68.7%)
|
3 (18%)
|
|
Pneumonitis
|
7 (43%)
|
1 (6%)
|
|
Rash
|
6 (37.5%)
|
2 (12%)
|
|
Pruritus
|
5 (31%)
|
0
|
|
Kidney dysfunction (elevated creatinine and/or hematuria)
|
3 (25%)
|
0
|
|
Fatigue
|
3 (25%)
|
0
|
|
Anorexia
|
1 (6%)
|
0
|
|
Endocrine disorder (hypothyroidism)
|
2 (12%)
|
0
|
The rate of treatment-related AEs was 68.7%. There were no Grade 4 AEs. The most frequent
AEs were fatigue, rash, and pruritus.
Discussion
The prognosis of patients with RM-SCCHN cancer after platinum-based chemotherapy is
very poor. [3]
Nivolumab is the first standard treatment for RM-SCCHN within 6 months after platinum
treatment.
Nivolumab demonstrated favorable OS, PFS, QOL, and RRs compared with standard chemotherapy
for platinum-refractory disease in a global phase III trial.[4]
In March 2017, nivolumab was approved for platinum-refractory patients in Japan and
has been used to treat recurrent metastatic squamous-cell carcinoma of the head and
neck. Zargar et al in Canada questioned its cost-effectiveness, although they pointed
out that a 20% reduction in price would lower the willingness-to-pay threshold.[7] Tringale et al, looking at the CheckMate 141 trial, found it to be lacking in cost-effectiveness.[8] In Japan, the potential indications for nivolumab are under discussion.
Nivolumab is a very expensive drug and we have to select the patients who could benefit
the most, possibly based on QOL years. Numerous searches for biomarkers suggestive
of response to therapy are being performed[9]; there have been no other reports on the influence of PD-L1 status on prognosis.
In the Asian population, the incidence of skin reaction was higher than the global
mean.[6] Our patients tended to suffer an increased incidence of recurrent skin reactions,
pneumonitis, and renal dysfunction compared with the global mean, although all were
Grade 1 to 2. The high pneumonitis incidence may have been due to the high proportion
of heavy smokers in our study.
Given the special immune-related AEs associated with monoclonal antibodies,[10]
[11] a multidisciplinary approach to treat them and to optimize therapeutic effectiveness
is needed. Being able to select patients most likely to respond may make this treatment
more cost-effective.
Limitations
The limitation of this study is its retrospective nature and the small number of subjects.
Conclusion
Our retrospective trial showed marginal improvement in survival in a small cohort
of Japanese patients. It remains to be determined which subsets of patients will benefit
from this treatment to the point that it is cost-effective.
