Trial Information

Tomotherapy Treatment for Mesothelioma

Background

Malignant mesothelioma of the pleura is one of the most challenging diseases to treat in
oncology. It is often associated with previous exposure to asbestos many years in the past
with the mean latency period between asbestos exposure and the development of mesothelioma
being approximately 48 years. The disease most commonly presents in the fifth to seventh
decade of life, and the natural history is one of relentless progression and eventual death
in nearly all patients. It can metastasize to regional nodes and/or distant sites, but most
of the morbidity and mortality comes from local disease in the chest, causing progressive
constriction, and death from pulmonary insufficiency or infection. Common clinical
manifestations can include pleural effusions, superior vena cava obstruction, dysphagia, and
laryngeal nerve palsy. Median survival rates are generally less than one year from the time
of diagnosis, although there may be a small subset of patients with more indolent disease
that have longer survival durations. Patients generally suffer from significant symptoms
over the course of their illness, particularly progressive dyspnea and chest pain.

Treatment options with mesothelioma

The treatment of mesothelioma has been characterized by disappointment. The only form of
"curative" treatment that has been attempted is a combination of surgery (extrapleural
pneumonectomy), chemotherapy, and radiation treatment to the hemithorax. This was described
by Sugerbaker, who reported 5-year survival rates of 22% of 120 patients treated.
Unfortunately, this approach is only possible for early stage disease (clinical stage I with
no nodal involvement) in the absence of comorbid medical illness, and the vast majority of
patients present with disease too advanced to consider this approach.

Role of radiotherapy in malignant mesothelioma:

Radiation therapy has been used with both radical and palliative intent. Radical treatment
with tumoricidal doses is difficult to achieve with conventional treatment machines due to
the dose limitations of normal tissues. The liver, heart, stomach, and normal lung tissue
is routinely encompassed within the planning target volumes and all of these tissues have
tolerances below the doses necessary to control disease. Curative (adjuvant) treatment has
also been given after extrapleural pneumonectomy, which does not have the problem of
underlying lung to deal with, but the other nearby normal structures are still difficult to
avoid.

A main component of the problem in both curative and adjuvant radiotherapy is the presence
of chest wall and diaphragm motion during radiotherapy. Breathing motion affects the chest
wall and diaphragm primarily, two of the principal targets in mesothelioma. Maneuvers such
as breath holding and respiratory gating, which have shown limited success in lung cancer
radiotherapy, are more difficult in mesothelioma due to the presence of significant dyspnea
and pain in a majority of patients. Clearly any attempt to treat the thoracic pleura with
high-dose radiotherapy must either limit or at least account for this organ motion.

The published results from treating mesothelioma with primary radiotherapy have been
suboptimal. High dose treatment to the hemithorax using conventional linear accelerators
has typically resulted in complete loss of function of the underlying lung, with no survival
benefit over palliative radiotherapy or no treatment. However, studies have suggested that
specific symptoms can be effectively palliated with focused radiation treatment. Gordon et
al reviewed 29 courses of palliative radiotherapy in 19 patients, with varying
dose/fractionation schedules. Overall 11/29 treatment courses resulted in complete,
"substantial", or partial relief of symptoms. Furthermore, palliation of symptoms strongly
correlated with doses over 40 Gy, suggesting a dose-response relationship. Other
investigators have shown effective palliation with lower doses. Davis et al treated
patients with 20-30 Gy in 4-10 fractions, with response rates of 60-68%. De
Graaf-Strukowska showed 50% pain response rates in patients treated to a mean dose of 36 Gy
at a minimum of 4 Gy per fraction.

These studies suggest that although radiation is an effective treatment modality against
mesothelioma, the technical difficulties in treating the pleural space effectively limit the
risk-benefit ratio.

Helical tomotherapy as a technique to treat mesothelioma

Tomotherapy is a relatively new technology which delivers intensity modulated radiation in a
helical fashion, much like a spiral CT scan. Because treatment is given from all angles
around a patient, the resulting dose distributions are highly conformal and effectively
reduce nearby normal tissues. Mesothelioma was identified early in tomotherapy's
development as an ideal site for this technology, since the target volume is extremely
difficult to treat using conventional techniques but well suited to the tangential beams of
tomotherapy. A test plan using tomotherapy to "treat" a sample patient resulted in
excellent dose coverage of the pleural disease with acceptable dose delivered to the
ipsilateral and contralateral lungs [unpublished data]. Nevertheless, these test plans were
designed on static systems in the absence of respiratory motion, so the feasibility of
treatment on breathing patients remains unproven. Tomotherapy is currently in routine
clinical and research use in several centres across North America, including the Cross
Cancer Institute where it was commissioned in 2003.

Study Objectives

Primary Endpoint

The primary endpoint is disease-specific symptom control rate post-treatment, based on
Palliation Index [Gordon 1982].

Secondary Endpoints

Overall survival Radiographic response rate at 3 months post-treatment Quality of life
scores (QLQ-L30) at 1-, 3- and 6-months post-treatment Acute and subacute toxicity of
treatment Feasibility of using cine-MR, using 3T-MRI, to define target volumes in
mesothelioma Performance status at 1-, 3- and 6-months post-treatment Pulmonary function
test results at 1-, 3- and 6-months post-treatment

Study Design

Description of the study

This is a single institution single-arm phase II study, assessing the efficacy of
tomotherapy-delivered radiation in patients with symptomatic mesothelioma. Patients are
treated with radiation alone (no concurrent chemotherapy), and assessed for symptoms and
performance status post-therapy.

Duration of study

Based on our statistical analysis (see below), we will require 14 analyzable patients. With
a potential drop-out rate of 20%, we will accrue 17 patients in total. Assuming a possible
accrual rate of one patient every 1-2 months, it may take 24-34 months to complete the
accrual process.

Selection of Patients

Eligibility Criteria

Histologic diagnosis of pleural mesothelioma Age>18 Life expectancy > 4 months Able to
breathe comfortably in a supine position for periods of approximately 20 minutes (with or
without supplemental O2) Has denied treatment with pemetrexed chemotherapy, or has evidence
of progressive or refractory disease on treatment with pemetrexed.

Not eligible or has declined aggressive multimodality (surgical) management for early-stage
disease Signed informed consent CT scan of chest performed within 6 weeks of study entry

Ineligibility Criteria

Any contraindications to thoracic radiotherapy In the judgment of the treating physician,
inadequate pulmonary reserve to tolerate the proposed radiotherapy.

Unable to perform shallow breathing in a manner to make tomotherapy delivery possible
Presence of symptomatic distant metastatic disease

Pre-treatment imaging

Pre-simulation imaging is required as part of this study in order to quantify the extent of
chest wall and diaphragm movement during the breathing cycle. Two approaches to this
analysis are acceptable: MR imaging (using the 3T MRI in the CBIAR facility) or
CT/fluoroscopy (using equipment in the radiation oncology department). The decision on
which technique to use will depend on the status of the MRI equipment for breathing
assessment at the time of patient accrual.

Patient follow-up and evaluations

Baseline 1- month 3-months 6-months History/physical a a a a PFTs a a a a PS a a a a
Palliation index a a a a QOL a a a a CT chest a a Planning MR imaging a

Statistical considerations

The number of patients required is based on the estimated efficacy of the proposed treatment
regimen and the desired level of statistical significance. The table below indicates the
relationship between these factors and the number of patients required:

Response rate Required "n" P-value 0.05 59 0.048 0.10 29 0.047 0.15 19 0.046 0.20 14 0.044
0.25 11 0.042 0.30 9 0.040

Based on the estimated response rate of the proposed treatment (ability to achieve some
relief of symptoms), if "n" patients are treated then at least one patient will demonstrate
a measurable response more than 95% of the time. In this study, an efficacy of 20% was
chosen as a worst-case scenario, below which the treatment would likely not be offered for
palliation. Therefore, 14 evaluable patients will be required to refute the null hypotheses
of the treatment being ineffective.

If the true efficacy rate is higher, then the likelihood of a false negative result is
lower, and an estimate of the true response rate can be learned.