Absorption of sublingually delivered fentanyl (Abstral) in head and neck cancer patients treated with curatively aimed chemo-or bioradiotherapy

In patients with head and neck cancer aggressive treatment strategies, e.g.
concurrent treatment with cisplatin or cetuximab and radiotherapy, lead to
local tumor control and an improved survival rate in comparison to radiotherapy
alone (1, 2). The consequences of this treatment with chemo- or
bioradiotherapy, however, are more toxicity problems like mucositis during
therapy and an atrophy and dry mouth (xerostomia) following therapy.
Due to the current standard treatment options, the majority of head-and-neck
cancer patients treated with curatively aimed chemo-or bioradiotherapy suffer
from severe mucositis. In these patients a mean mucositis incidence of 80% is
thought to be quite common (3).. Mucositis may lead to severe pain, significant
weight loss, need for a feeding tube, hospitalization, and, as a result,
increased costs(3, 4). In patients receiving conventionally fractionated
radiotherapy (in combination with cisplatin) a median duration of severe
mucositis (WHO grade 3-4) of 26 days has been reported. The median time to this
severe form of mucositis was found to be 35 days(5). Both the radiotherapy dose
and its localization are correlated with the severity and duration of the
mucositis. Cumulative doses in the oral cavity less than 32 Gy were associated
with minimal mucositis and doses of 39 Gy and more with a longer duration of
mucositis(6).

Besides mucositis, xerostomia is a major problem in head and neck cancer
patients treated with radiotherapy. This is due to iradiation of the salivary
glands. Xerostomia is the worst six weeks after radiotherapy treatment has
finished. Xerostomia improved in time after radiotherapy, in a study during a 5
yr period of follow up, but did not return to baseline (7).

From the third week of radiotherapy, oral pain is getting serious, and will
require analgesics(8). Mucositis is increasing in the weeks following and worst
at the end of radiotherapy treatment. Despite the wide use of opioids this pain
is not always sufficiently controlled(8, 9).

For moderate-severe pain, opioids are indicated. International guidelines
advice the use of a combination of slow-release and immediate release opioids;
the last ones on demand in case of increasing pain. Because of mucositis, and
therefore problems with swallowing, the use of oral medication can be difficult
and painful. Transdermal patches like the patches with buprenorfine and
fentanyl or subcutaneously delivered morphine or fentanyl are preferred for
treatment of continuous pain in mucositis. For the treatment of breakthrough
pain several immediate release products are available like short-acting
morphine, oxycontin and nowadays several oromucosal fentanyl products.

Fentanyl is one of the most widely used opioids. This drug is highly lipophilic
and binds strongly to plasma proteins. In addition, fentanyl is more potent
than morphine at equipotent dose levels (10). The metabolism of fentanyl takes
place primarily in the liver (11). Fentanyl is mainly oxidized into the
inactive metabolite norfentanyl by the CYP3A4 iso-enzyme(12). Less than 1% is
metabolized to despropionyl-fentanyl, hydroxyfentanyl, and hydroxynorfentanyl.
These metabolites are also inactive. Fentanyl is mainly excreted renally. The
large majority of the fentanyl is excreted as metabolites, while 10% is
excreted as unchanged drug. A minority of fentanyl is found in the feces,
mainly as metabolites (11).

Abstral® is a sublingual form of fentanyl and is one of the new immediate
release oromucosal fentanyl products for the treatment of breakthrough pain
episodes. Abstral® is placed directly under the tongue, in the deepest part.
It will be absorbed by the mucosa. Sublingual fentanyl is well tolerated in
patients in a placebo controlled study(13).

Unfortunately, it is unclear if the level and rate of absorption of
sublingually administered fentanyl is influenced by mucositis. In healthy
subjects, sublingually delivered fentanyl is immediately absorbed by the
sublingual mucosa. First detectable plasma concentrations are found around 10
minutes after administration. A part of the dose is absorbed by the
gastrointestinal tract. Median Tmax is around 40 minutes(14).

Sublingually delivered fentanyl has not yet been tested in patients with
mucositis. Buccally delivered fentanyl was tested in patients with mild
mucositis (grade 1) in two small studies, including in total14 (7 patients with
mucositis) and 16 (8 patients with mucositis) patients, respectively. In both
studies 200 mcg buccal fentanyl was used. In one study patients were opioid
naïve. In neither of these studies serious adverse events occurred. These
studies showed no difference in fentanyl concentrations between patients with
and without mucositis. Besides the small sample size, only inter-patient
comparisons (between patients with and without mucositis) were performed and
only patients with mild (grade 1) mucositis were included (15, 16). Knowing the
inter-patient variability (14, 16) in serum concentrations using the same dose
of fentanyl, it is impossible to draw hard conclusions on the influence of
mucositis on the absorption of sublingual fentanyl in such small studies. It is
also not clear if xerostomia influences absorption of sublingually delivered
fentanyl, although the advice is to rinse the mouth with water before taking
Abstral ® when suffering from a dry mouth (17).

In studies with buccally and sublingually delivered fentanyl in healthy
volunteers, doses up till 200 mcg were studied without significant side effects
and safety problems (9). When more than 200 mcg fentanyl was used, naltrexone
was co-administered(18) . Co-administration of naltrexone minimizes the opioid
receptor mediated effects of fentanyl. This combination of drugs would not be
expected to affect the pharmacokinetics of fentanyl because fentanyl is a
substrate of CYP3A4 and naltrexone is not (19). Other studies with buccally and
sublingually delivered fentanyl were done in opioid tolerant patients.

Primary Objective:
- To study the effect of mucositis on the absorption of sublingually delivered
fentanyl (Abstral®) in head and neck cancer patients treated with
chemoradiotherapy.


Secundary Objective:
- To study the effect of xerostomia on the absorption of sublingually delivered
fentanyl (Abstral®).
- To study the relation between radiotherapy dose sublingual and the changes in
pharmacokinet ics

This is a single-center pharmacokinetic study. The trial will be performed at
the Erasmus MC-Daniel den Hoed Cancer Center, Department of Medical Oncology.
Patients will be given a single dose of Abstral® 200 mcg sublingually.
Pharmacokinetics of sublingually delivered fentanyl will be measured at 4
different time points: at or within 3 days before start of the radiotherapy
(T=0), 18-21 days after starting radiotherapy (T=1), 39-42 days after starting
(T=2) and six weeks after the end of the chemo- or bioradiotherapy (T=last).
For patients* convenience, and therefore feasibility of the study, study
procedures will be planned as far as possible at days patients are visiting the
hospital for treatment, information or other reasons.
Pharmacokinetic samples will be taken pre-dosing, at 10, 20, 30, 40, 50, 60,
90, 180 and 360 minutes after the single Abstral ® l dose.

Radiotherapy: Patients will be given 70 Gy to the primary tumor and clinically
positive nodes, given in 35 fractions of 2 Gy each over a seven-week period
(elected lymph node areas are irradiated with a minimum of 46 Gy). The
radiotherapy dose in the sublingual area will be measured by the radiation
oncologist.

Patients treated with cisplatin stay in the hospital during 24 hrs. Cisplatin
(100 mg/m2) solved in natriumchloride 3% is given in 3 hours. For anti-emetic
prophylaxis patients receive a regimen consisting of oral aprepitant 125 mg
plus i.v. dexamethasone 10 mg and i.v. granisetron 1 mg on day 1 15 minutes
before the administration of cisplatin, aprepitant 80 mg and oral dexamethasone
6 mg once daily on day 2-3, and dexamethasone 6 mg on day 4. Patients are pre-
and posthydrated with glucose 2.5%, natriumchloride 0.45% in combination with
potassiumchloride during 24hrs.

Patients treated with cetuximab stay in the hospital during 4 hrs. Patients
receive a loading dose of 400mg/m2 i.v 1 week prior to radiotherapy and then
seven weekly infusions of 250 mg/m2 during radiotherapy, the first 250 mg/m2
infusion at the start of radiotherapy. For anti-allergy prophylaxis patients
receive clemastin 1mg prior to cetuximab treatment.

Pain scores will only be documented when patients have pain at the start of the
pharmacokinetic sampling. In these patients pain will be scored again 1 hour
after administration of Abstral. Pain will be scored according the Numeric
Rating Scale (NRS).

General toxicity will be scored before the pharmacokinetic sampling and 1 hour
after administration of Abstral Toxicity will be scored according te NCI-CTC v
4.3 toxicity criteria (Appendix B).

Mucositis will be scored according the NCI-CTC v 4.3 toxicity criteria
(Appendix C) and the Oral Mucositis Assessment Scale, OMAS. The OMAS is easy to
use and showed a high interobserver reproducibility (correlation coefficient
>0.92),(20) Appendix D).

Xerostomia will be scored according the Groningen Radiotherapy-induced
Xerostomia questionnaire (GRIX). The Grix is a validated questionnaire (21)
(Appendix E).

When patients need analgesics they can use all opioids except immediate and
slow release fentanyl. For continuous pain the buprenorfine is preferred
because of the transdermal administration route. Oxynorm and oramorph can be
used for breakthrough pain. Otherwise, subcutaneous morphine can be used in
case of side effects or inadequate pain relief on buprenorphine. When fentanyl
is deemed necessary, patients will get off study.
General toxicity will be scored according the NCI-CTC toxicity criteria, before
taking Abstral ® and 30 and 60 minutes after taking Abstral ®.
Naltrexone is available for use in case of rare serious side effects.

- administration of sublingual fentanyl

low