Trial Information

Dexamethasone for the Prevention of a Pain Flare After Palliative Radiotherapy for Painful Bone Metastases: a Multi-center Double-blind Placebo-controlled Randomized Study

Background of the 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?

Study design:

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.