Dexamethasone for the prevention of a pain flare after palliative radiotherapy for painful bone metastases: a multicenter double-blind placebo-controlled randomized study.

Patients with pain due to bone metastases are often treated with palliative
short schedule external beam radiotherapy. Dependent on the institutional
protocols, single fraction (8 Gy) or 5-6 fractions of 4 Gy are usually applied.
Randomized studies have shown the equal effectiveness of both schedules in
treating pain, with almost 70% of patients experiencing less or no pain within
three to four weeks after treatment (Wu 2003). However, within 10 days after
treatment a short term transient progression of pain may occur, the so-called
pain flare (Chow 2005, Loblaw 2007, Hird 2009-1).
Two prospective observational studies reported patient-based daily pain scores
after radiotherapy for painful bone metastases. Loblaw showed a pain flare in
44% patients after 8 Gy and in 24% patients after 20 Gy in 4 fractions (Loblaw
2007). The median duration of the pain flare was three days. A recent
publication found no difference in pain flare in 111 patients after single vs.
multiple fractions (39% vs. 41%, resp.) (Hird 2009-1). No data are available of
the occurrence of pain flare in Dutch patients. The largest trial to date on
painful bone metastases, the Dutch Bone Metastasis Study, was funded by OG and
CKTO and randomized from 1996-1998 a total of 1157 patients between 8 Gy single
fraction and 24 Gy in 6 fractions (PhD thesis, van der Linden 2005). Follow-up
consisted of 12 weekly and thereafter monthly questionnaires on pain, pain
medication and quality of life. In this study, daily scoring of pain to asses
pain flare was not performed.
When a pain flare occurs oral dexamethasone can be prescribed. The rationale
for administering steroids is to decrease edema that arises in the periostium
of the affected bone shortly after radiotherapy and thereby to reduce pain (de
Graeff 2006). Two small studies were performed to study the effectiveness of
dexamethasone for treating a pain flare (Chow 2007, Hird 2009-2). Chow et al.
administered 8 mg dexamethasone to 23 patients one hour before single fraction
treatment and showed pain flare in only 24% of patients (95% CI 10-39%) within
the first 10 days after radiotherapy (Chow 2007). Only one patient had a flare
within two days after treatment. Dexamethasone was well tolerated. In a fase 2
study of the same research group 41 patients were administered 8 mg
dexamethasone before and then for three consecutive days after single fraction
treatment. They showed a pain flare in 22% of patients (with a median duration
of one day), with 81% occurring within five days after treatment, and 95%
within 10 days (Hird 2009-2). Both studies concluded that randomized studies
are necessary to collect unbiased data on the occurrence and duration of pain
flare and the effectiveness of drug treatment. Until now, no randomized studies
were performed comparing dexamethasone with placebo or no treatment. The
effectiveness of placebo vs. dexamethasone in the treatment of pain flare in
patients after radiotherapy for painful bone metastases is the subject of this
study.

Aim of the study
To study the effectiveness and toxicity of dexamethasone to prevent the
occurrence of a pain flare after short schedule radiotherapy for painful bone
metastases and to define the optimal schedule of dosing.
Research questions:
1. What is the effectiveness of dexamethasone to prevent the occurrence of a
pain flare after short schedule radiotherapy for painful bone metastases?
2. Is there a difference in effectiveness between a single dose of 8 mg
dexamethasone before radiotherapy or a dose of 8 mg dexamethasone before
radiotherapy in combination with three additional doses during the three
following days?
3. What are the side effects of dexamethasone and placebo in patients treated
with radiotherapy for painful bone metastases?
4. Does a pain flare predict for pain response to radiotherapy?

This study is a randomized, controlled, multicenter study in 411 patients with
painful bone metastases who are referred for a short course of palliative
radiotherapy. Short course radiotherapy encompasses all treatment schedules
from one to six fractions of radiotherapy.
The study consists of three arms:
* Arm 1: day 0: placebo, day 1, 2 en 3: placebo
* Arm 2: day 0: 8 mg dexamethasone, day 1, 2 en 3: placebo
* Arm 3: day 0: 8 mg dexamethasone, day 1, 2 en 3: 8 mg dexamethasone
Day 0 is the first day of radiotherapy treatment. On day 0 the tablet of
placebo or dexamethasone will be administered one hour before radiotherapy. On
day 1, 2, and 3 the tablet of placebo or dexamethasone will be taken in the
morning at about 8 a.m.

Patients will be treated with dexamethasone and/or placebo orally during four
days:
* Arm 1: day 0: placebo, day 1, 2 en 3: placebo
* Arm 2: day 0: 8 mg dexamethasone, day 1, 2 en 3: placebo
* Arm 3: day 0: 8 mg dexamethasone, day 1, 2 en 3: 8 mg dexamethasone
All patients will receive radiotherapy (1-6 fractions).

The burden and risks of the study are mainly related to the intake and
side-effects of dexamethasone and placebo and to having to complete a
questionnaire daily during 14 days and at day 28. Because of the short
duration of treatment with dexamethasone, only minor side effects (increased
appetite, irritability and insomnia) are expected to occur. Study burden is
expected to be low.
If oral administration of dexamethasone effectively reduces short-term pain
flare in patients treated with palliative radiotherapy for painful bone
metastases, it will be implemented into the daily practice of radiotherapy
institutions throughout the Netherlands, resulting in decreased incidence and
duration of pain flare after radiotherapy for painful bone metastases.