ARTICLE
Auteur(s) : Rohit Malde1, Jai Prakash Agarwal1,
Sarbani Ghosh Laskar1, Tejpal Gupta2, Ketayun
Dinshaw1
1Department of Radiation Oncology, Consultant
Radiation Oncologist, 118, Tata Memorial Hospital, Dr Ernest Borges
Marg, Parel, Mumbai 400012, India
2Department of Radiation Oncology, ACTREC, Navi Mumbai,
India
Nasopharyngeal carcinoma (NPC) represents a distinct entity amongst
head and neck cancers, in terms of its epidemiology, pathology,
clinical features, treatment and outcome. It has a high incidence
in several areas in southern China, especially in the Cantonese
region around Guangzhou, where the incidence is approximately
30-80/100,000 population per year [1]. Other areas of high
incidence include Taiwan, Vietnam, Philippines and the
Mediterranean region (Maghreb and Malta). In India, NPC constitute
less than 1% of all head and neck cancers [2]. A majority present
with advanced stages [2]. According to The World Health
Organization (WHO), nasopharyngeal carcinoma is of three types:
keratinizing squamous cell carcinoma (WHO type 1);
nonkeratinizing carcinoma (WHO type 2) and undifferentiated
carcinoma of nasopharyngeal type (WHO type 3). The standard
treatment for primary NPC is radical radiotherapy with or without
chemotherapy, as surgery is generally not feasible due to the
peculiar location of the nasopharynx. This anatomic site lies in
close proximity to critical structures such as the spinal cord,
optic apparatus, pituitary gland, hypothalamus and the temporal
lobes, which could lead to significant morbidity. Although NPC are
relatively radiosensitive tumors, they are one of the most
technically difficult sites within the head and neck region to
treat.Treatment with radiotherapy alone results in local control
rates between 85-90% for early stage disease (T1-2, N0) and 44-71%
for advanced stage disease (T3-4, N+) [3]. Advanced NPC have a
higher incidence of distant metastases compared to other head and
neck cancers ranging from 17 to 48% [3]. Despite high initial
complete response rates, a significant proportion of patients
relapse locally [4]. In an attempt to improve local control and
reduce distant metastases, chemotherapy has been combined with
radiotherapy with encouraging results. The Intergroup trial
demonstrated a significant reduction in local and distant relapses
resulting in an improved 3-year overall and progression-free
survival using concomitant and adjuvant cisplatin-based
chemotherapy [5]. Local control has also been shown to be an
independent marker of distant metastasis [6]. Escalation of the
radiation dose is an attractive option for improving local control
of primary disease. The rationale for this approach is based on a
general trend towards improved local control with higher doses of
radiation as shown in several retrospective studies [7-9]. Dose
escalation has been accomplished using both external beam radiation
therapy (EBRT) and brachytherapy (BT). Delivering a higher
radiation dose to the nasopharynx using conventional EBRT
techniques could result in excessive morbidity such as trismus,
osteoradionecrosis, visual impairment, brain necrosis, decreased
hearing, radiation caries and severe dry mouth. However with
sophisticated, high precision techniques such as 3-Dimensional
conformal radiotherapy (3DCRT), stereotactic
radiosurgery/radiotherapy (SRS/SRT) and intensity modulated
radiotherapy (IMRT), this task can be achieved with acceptable
toxicity [10, 11].Brachytherapy has the advantage of rapid dose
fall off, which enables the radiation oncologist to deliver a
higher tumor dose while sparing the nearby critical dose-limiting
structures. The ingenuity of clinical researchers to treat this
secluded anatomical midline structure by brachytherapy is
exemplified by the numerous technical endeavors in the form of
transpalatal interstitial implantation with gold grains or
iodine125 seeds and different intracavitary applicators using
137Cesium, 60Cobalt, 192Iridium
with either low dose or high dose rate (HDR) systems. Recent
developments in BT such as pulsed dose rate and HDR computerized
afterloaders, and sophisticated treatment planning systems with
optimization capabilities, have even further encouraged the
evolution of intracavitary BT afterloading techniques [7]. Whereas
BT has an established role in the treatment of locally recurrent
and persistent disease [12-14], its benefit as an adjuvant boost
following EBRT has not been completely elucidated.At the Tata
Memorial Hospital, since 1998 with the availability of Rotterdam
silicone nasopharyngeal applicator (RSNA) we have attempted to
deliver an intracavitary boost with HDR for carefully selected
patients with NPC. We report our prospective preliminary experience
of this technique in 10 patients with primary NPC.
Methods and materials
Between 1998 and 2003, 10 patients diagnosed with primary NPC were
prospectively evaluated for the HDR-BT boost following radical EBRT
with or without chemotherapy. Patients with complete clinical
response at the nodal site and either a complete response or good
partial response at the primary site were considered suitable for
HDR-BT and included in this study. Pretreatment evaluation of all
patients consisted of a complete history and physical examination,
including nasopharyngeal endoscopy followed by a biopsy, complete
blood counts, liver and renal function tests, chest x-ray, imaging
of the nasopharynx and the neck with either computerized tomography
scan (CT scan) or magnetic resonance imaging (MRI) and dental
evaluation. All patients were staged according to the 1997 American
Joint Committee on Cancer (AJCC) staging classification [15].
Following EBRT, response was assessed clinically and selected
patients scheduled for HDR-BT.
EBRT
All patients were simulated and planned in a customized
thermoplastic mask in the supine position. EBRT was delivered using
Cobalt-60 or 6 MV photons with bilateral parallel-opposed portals
with appropriate shielding. The spinal cord was shielded after 46
Gy/ 23# and posterior neck electron boost was used whenever
indicated. The total dose of EBRT thus delivered was 60-70 Gy/30-35
#/6-7 weeks (median 66 Gy).
Chemotherapy
Patients with early stage NPC (stage I and II) were treated
with radical radiotherapy alone (n = 2) or concomitant cisplatin
based chemoradiotherapy (n = 3). Patients with advanced NPC (stage
III and IV) were treated with 2-3 cycles of cisplatin based
neoadjuvant chemotherapy followed by concomitant chemoradiotherapy.
HDR-BT
Two to four weeks after completion of EBRT, patients were assessed
for a brachytherapy boost. HDR-BT was delivered with an
192Iridium afterloading unit (microSelectron HDR,
Nucletron). The technique of HDR-BT and the prescription dose to
the nasopharynx point were employed as described by Levendag et al.
[16]. Briefly, under sedation and topical anesthesia, a pair of
infant feeding tubes were inserted as guide tubes, one through each
nostril into the nasopharynx and pulled out gently through the
mouth using MacGill’s forceps. The lubricated RSNA was then
inserted intra-orally over these guide tubes and pulled through the
nostrils so that it fitted snugly in the nasopharyngeal space. The
patient was then simulated supine with head in neutral position,
lead markers on the lateral canthi and tragus and dummies in the
tubes. After determining the length to be treated, various points
(tumor points as well as normal points) described by Levendag were
marked on orthogonal films and dose prescribed to the
nasopharyngeal point (( figure 1 )). Dose
point optimization was employed to achieve satisfactory dose
distribution. Typically, two HDR fractions separated by at least 6
hours were delivered each day for 2 consecutive days with a total
dose of 14 Gy in 4 fractions (4-3-3-4 Gy). The median dose
delivered with HDR-BT was 12 Gy (range: 5-14 Gy in 1-4 fractions)
Follow-up
After the completion of radiotherapy, all patients were evaluated
every 3 months for the first year, every 6 months for the next 3
years and annually thereafter. At each follow up visit, a complete
physical examination, including direct and/or indirect
nasopharyngeal endoscopy was performed. A baseline post-treatment
CT/MRI imaging of the nasopharynx and the neck was obtained at
first follow-up and was performed subsequently only if clinically
indicated. The acute and the late effects were graded according to
the Radiation Therapy Oncology Group (RTOG) radiation morbidity
scoring criteria [17].
Statistical methods
Descriptive statistics (mean, median and proportions) were
calculated to characterize the patient, disease and treatment
related factors. The duration of time to loco-regional failure and
distant metastasis was calculated from the last date of
brachytherapy until documented treatment failure. The duration of
overall survival was also calculated from the date of brachytherapy
until death or until the last follow-up date for those patients
still alive. The disease free survival (DFS) was calculated using
the Kaplan Meier method.
Results
The patient and treatment characteristics of the 10 patients
treated with HDR-BT are shown in tables 1 and 2( Table 1 )( Table 2 )
respectively. The median age at presentation was 49 years (range
17-66 years). Six (60%) patients presented with T1-T2 disease,
whereas the other 4 (40%) had T3-T4 stage. Eight (80%) patients had
clinical cervical lymphadenopathy. The majority (60%) of these were
squamous carcinomas whereas undifferentiated carcinomas of
nasopharyngeal type (WHO type 3) constituted the other 40%.
None of the patients had distant metastases at presentation.
Patterns of failure
Of the 10 patients treated, 6 patients were found to be
disease-free and alive at the last evaluation. Of the remaining 4
patients, one patient who initially had an incidental premalignant
lesion (leukoplakia) developed a second primary in the lower
alveolus 8 months following treatment of the primary NPC, another
patient had persistent local disease even after brachytherapy,
while 2 other patients developed distant metastases in the lung and
bones respectively. The former two patients succumbed following
progression of the disease and the latter 2 patients are undergoing
palliative chemotherapy. With a median follow up of 28 months
(range 5-66 months), the local control was 90%. The estimated
3-year disease-free survival was 60% (( figure 2 )).
Table 1 Nasopharyngeal carcinoma: patient
characteristics
|
Patient characteristics
|
Patients (nb)
|
|
Age (years)
|
≤ 50 years
|
6
|
|
> 50 years
|
4
|
|
Sex
|
Male
|
7
|
|
Female
|
3
|
|
Tumor Status
|
T1-2
|
6
|
|
T3-4
|
4
|
|
Nodal Status
|
Node positive
|
8
|
|
Node negative
|
2
|
Table 2 Radiotherapy schedule (EBRT + HDR-BT) schedule
used in NPC
|
EBRT dose
|
Median 66 Gy (range 60-70 Gy)
|
|
Interval between EBRT and HDR-BT
|
Median 34 days (range 6-102 days)
|
|
HDR-BT total dose
|
Median 12 Gy (range 5-14 Gy)
|
|
HDR-BT dose per fraction
|
3-5 Gy
|
|
Number of HDR-BT fractions
|
1-4 fractions
|
Acute and late toxicity
All the patients tolerated external radiotherapy fairly well with
the most common acute side effects being mucositis. There were only
2 patients who developed RTOG grade-III mucositis. There was no
grade III-IV hematological toxicity in patients who had received
either neoadjuvant or concurrent chemoradiotherapy. All patients
completed treatment without significant delay due to toxicity. In
terms of late toxicity, the most common side effect was mild to
moderate xerostomia which was seen in almost all our patients.
There were no significant late toxicities directly attributable to
brachytherapy except one patient who had persistent crust formation
in the nasal mucosa.
Discussion
Nasopharyngeal carcinomas due to their peculiar location are an
interesting and challenging site for any radiation oncologist to
deliver an adequate tumoricidal dose without causing excessive
complications. In an attempt to improve the local control, various
investigators have performed dose escalation studies with both
external beam radiation therapy and brachytherapy. Due to the rapid
dose fall-off, nasopharyngeal brachytherapy has the capability to
deliver high tumor dose with minimal dose to the surrounding
healthy critical tissues. Reports in literature on the adjuvant use
of brachytherapy in primary NPC are generally retrospective [7, 12,
18-24] consisting of a small cohort of patients with heterogenous
tumors and treatment parameters with variable follow up periods
(table 3( Table 3 )). Lack of any
prospective randomized trials makes it difficult to reach a
definitive conclusion regarding the role of adjuvant brachytherapy
in this group of patients. Despite these limitations, there seems
to exist a dose response relationship with adjuvant brachytherapy,
above the conventional radical doses of 66-70 Gy, as shown by some
authors [17, 18, 25].
Improved results with brachytherapy were first reported in China
in 1980 by Chang et al. [24]. A significant benefit in terms of
local control and survival at 5 years was reported when low dose
rate brachytherapy was added to conventional external radiotherapy.
Teo et al. [18] clearly showed the existence of a dose response
relationship above the conventional tumoricidal dose. Patients with
early stage NPC (T1-2) were treated with external RT 60 Gy followed
by HDR boost 18-24 Gy in 3 fractions. Of the 163 patients treated,
there were 101 patients with persistent disease at 4-6 weeks after
EBRT. These patients were compared with a similar cohort of
patients (n = 346) treated with EBRT alone. The authors observed a
5-year actuarial local control rate of 94.5% for patients treated
with adjuvant brachytherapy compared to 89.7% for patients treated
with EBRT alone. They concluded by stating that supplementing EBRT
with adjuvant brachytherapy with an uncorrected BED ≥ 75 Gy would
significantly enhance the ultimate local control with minimal and
manageable toxicity such as ulceration and necrosis.
Recently, Lu et al. [25] in a prospective protocol of newly
diagnosed T1-2 staged NPC treated 16 patients with EBRT (66Gy)
and concurrent cisplatin based chemotherapy followed by adjuvant
cisplatin and 5-fluorouracil chemotherapy. HDR-BT boost of 10 Gy
was delivered in 2 weekly fractions after the completion of
EBRT. At a median follow-up of 18 months, 15/16 (93.8%) patients
were loco-regionally controlled. In a recent update the authors
reported on 33 consecutive and nonselected patients with T1-2
NPC, including the 16 patients from their preliminary report. At a
median follow-up of 29 months (range 17-38), one patient (3%) had
persistent local disease; one patient (3%) had pathologically
confirmed local recurrence. In addition, one patient (3%) developed
a neck node followed by distant metastasis, and two patients (6%)
developed distant metastasis without locoregional relapse. The
2-year local control rate at the primary site was 93.6%, and the
overall survival and disease free survival rates were 82% and 74%,
respectively [26]. Ten patients (30%) developed grade 3 acute
and/or late toxicity, and six patients (18%) developed grade 4
acute and/or late toxicity. No grade 5 toxicity occurred.
Our 3-year local control rate and DFS was 90% and 60%,
respectively which seems to be comparable with the published data.
There was only one patient with persistent local disease. The
remaining 9 patients are locally controlled. There was only 1
patient with persistent soreness and crust formation in the nasal
mucosa due to synechiae formation which responded to topical
emollients. All other patients tolerated adjuvant brachytherapy
well with no major toxicity. Patients with early stage disease and
selected patients with advanced stage disease with remarkable
response to combined chemo-radiotherapy can be treated with
adjuvant brachytherapy. T4 disease with intracranial extension or
significant parapharyngeal extension may not be a good situation
for brachytherapy because of the risk of tumor underdosage and/or
major complications. In the latter case, dose escalation in the
form of IMRT or SRS/SRT boost may be helpful in improving outcome
[10, 11].
Table 3 Literature review of primary NPC treated with
HDR-BT boost
|
Author [Ref]
|
T- Stage
|
Dose (Gy)
|
Chemo-therapy
|
5-yr local control
|
5-yr survival
|
|
EBRT
|
Brachytherapy
|
|
Chang [20] 1996
|
T1-2 (133)
|
64.8-68.4 Gy
|
HDR: 5-16.5 Gy/ 1-3 # @ 2 cm off axis
|
Nil
|
< 72.5 Gy : 73%
|
72%
|
|
72.5-75Gy: 94%
|
92%
|
|
> 75 Gy : 79%
|
77%
|
|
Slevin [22] 1997
|
|
45-60 Gy
|
HDR: 5-7.5Gy/ 1#
|
Nil
|
87% (3y)
|
|
|
Levendag [7] 1998
|
- T1 = 3, T2 = 9
- T3 = 17, T4 = 13
|
|
- T1-3: 18Gy/6 #
- T4: 16Gy/4 #
- @ 1 cm off-axis
|
1 (2.5%)
|
86% (3y)
|
71% (3y DFS)
|
|
Syed [12] 2000
|
- T1 = 1, T2 = 4
- T3 = 6, T4 = 4
|
50-60 Gy
|
HDR Implant: 33-37 Gy
|
5 (33%)
|
59%
|
|
|
Teo [18] 2000
|
|
60 Gy
|
HDR:18-24 Gy / 3# @ 1cm off-axis
|
10 (6%)
|
93%
|
88% (5y DFS)
|
|
De Nittis [23] 2002
|
T1-T3 = 11
|
|
HDR: 6-15 Gy / 1-2 # @ 0.5 cm
|
11 (100%)
|
100% (3y)
|
100% (3y OS)
|
|
Lee [19] 2002
|
|
54-72 Gy
|
HDR 5-7Gy/1-2 # LDR: 10-54 Gy.
|
17 (40%)
|
89%
|
|
|
Levendag [17] 2002
|
- T1 = 7, T2 = 39
- T3 = 11, T4 = 14
|
60-70 Gy
|
HDR: 11-18 Gy / 4-6 # @ 1 cm off axis
|
20 (41%)
|
- I-IIB: 100% (2y)
- III-IVB: 86% (2y)
|
- I-IIB: 90% (2y DFS)
- 61% (2y OS)
- III-IVB:74% (2y DFS)
- 66% (2y OS)
|
|
Ozyar [21] 2002
|
- T1 = 45, T2 = 32
- T3 = 13, T4 = 16
|
58-71 Gy (65.4 Gy median)
|
HDR: 12 Gy/3 # @ 1 cm off-axis
|
55 (51%)
|
86% (3y)
|
- 76% (3y CSS)
- 67% (3y DFS)
|
|
Lu [26] 2004
|
|
70 Gy
|
HDR: 10 Gy/2 # @ 1 cm off axis
|
33 (100%)
|
93.6% (2y)
|
- 74% (2y DFS)
- 82% (2 y OS)
|
|
|
60-70 Gy
|
HDR: 5-14 Gy / 1-4 # @ 1 cm off axis
|
8 (80%)
|
90% (3y)
|
60% (3y DFS)
|
Conclusion
The small number of patients in our report precludes any definitive
conclusions. Nevertheless it appears that HDR-BT following radical
EBRT with or without chemotherapy is an efficacious boost modality
with acceptable morbidity in a select group of patients with NPC.
Our patterns of failure suggest that further adjuvant chemotherapy
following completion of concurrent chemoradiation could also be
considered for patients at high risk of distant relapse. However
this strategy requires to be tested and validated in large
prospective randomized control trials before its routine
application in the clinic.
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