Hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

Presenter: Dr. K. Tsuboi
Presenter's Affiliation: Proton Medical Research Center, University of Tsukuba, Tsukuba, Japan
Type of Session: Scientific

Background

Despite aggressive multimodality treatment, outcomes in glioblastoma (GBM) remains poor, with a two year survival of approximately 25% (Stupp, NEJM, 2005)
In order to try and improve on these results, several groups have investigated the use of higher doses of radiation in the treatment of GBM using stereotactic techniques or proton therapy
Fitzek et al. (1999) used a combination of photon- and proton-based hyperfractionated therapy to a total dose of 93.5 CGE and found a median survival of 20 months
Based on the results of these studies, the use of hyperfractionated proton therapy for the treatment of GBM was investigated by this group
This group also correlated histological and immunohistochemical changes with changes in enhancement seen on MRI imaging to determine the cause of changes in the enhancing areas on MRI

Materials and Methods

Study entry criteria:
- Patients with newly diagnosed GBM
- Patients between 20-80 years of age
- Patients with visible tumor residual on MRI imaging performed within 72 hours of surgery
- Patients had to have a KPS of greater than 60
- The diameter of the enhancing area of the tumor could not be larger than 4 cm prior to radiation therapy
- Areas of enhancement could not involve the brainstem, hypothalamus or thalamus
Radiation Therapy:
- Bid dosing was used, with a conedown during the second half of treatment
- Clinical target volume (CTV2):
  - CTV2 was defined as the areas of increased T2 signal
  - CTV2 was treated using photon therapy to a dose of 50.4 Gy in 28 fractions
  - PTV2 was defined as CTV2 plus a 5 mm margin
- CTV1:
  - PTV1 was treated more than 6 hours after treatment of PTV2
  - 250 MEV proton therapy was used to treat PTV1
  - For the first half of treatment, PTV1 was treated
  - CTV1 was defined as the are of enhancing volume plus a 10 mm margin
  - PTV1 was defined as CTV1 plus a 5 mm margin
- GTV:
  - For the second half of treatment, PTV0 was used to define the boost volume
  - The GTV was defined as the enhancing area without margin
  - PTV0 was defined as the GTV plus a 5 margin
- 23.1 CGE in 14 fractions was delivered over the entire course of treatment to the two boost volumes, resulting in a total dose of 96.6 CGE to PTV0
Chemotherapy:
All patients received ACNU (80 mg/m2), and this was given during the first and the fourth weeks of radiation therapy

Results

Twenty-four patients with histologically confirmed supratentorial GBM’s who met the above mentioned entry criteria were enrolled on this study
Median age was 55 years of age, and there were 14 men and 10 women
16 patients had a subtotal resection
Median volume of PTV1 was 92.5 cc
Patients were serially imaged on MRI to quantify changes in the enhancing volume, and correlations were made between changes in volumes and histological factors, such as Ki67, apoptosis, autophagy, vascular endothelial growth factor (VEGF) and CD133 using immunohistochemistry
Toxicity:
- Acute toxicity was mostly hematologic and treatment was well tolerated
  - Six patients required GCSF
  - One patient had to have treatment held due to cholecystitis, no treatment related delays were seen
  - Five patients required steroids during treatment
- Late toxicity: leukoencephalopathy and necrosis were each seen in one patient
Overall survival was 77.6% and 44.5% at 1 and 2 years, respectively
Median overall survival was 20.9 months
Cause specific survival was 81.1% and 50.7% at 1 and 2 years, respectively
Median cause specific survival was 24.5 months
Imaging related analysis:
- In five patients there were no imaging related changes at a median follow up of 19.3 months
- In 19 patients there were changes in follow-up MRI’s at a median time of 6.6 months
  - Of these, seven were felt to be in-field recurrences, six were felt to be bordering the field, and six were felt to be outside of the treatment field
  - Data from the seven patients with in-field recurrence, who underwent repeat resection, suggested that there were necrotic and inflammatory cells, along with degenerating tumor stem cells in the areas of enhancement. It was felt that these tumor stem cells were unlikely to be viable based on immunohistochemical staining
  - These conclusions were partially based on a decrease in Ki67 positivity, with a moderate increase in apoptosis and autophagy seen on immunohistochemical staining. There was also noted to be a relative increase in VEGF and CD133 positivity in tissue taken from the second surgery

Author's Conclusions

The results from this study suggests that a hyperfractionated concomitant boost technique using protons to a dose of 96.6 CGE is tolerable from an acute and late toxicity perspective
Results from this study compare favorably with prior study outcomes
Early increases in enhancing volume appear to be due to treatment-related changes with necrosis and inflammation noted post-treatment. However, there were noted to be tumor stem cells as well, although they did not appear viable. These patients should be followed closely and not assumed to have progression
The authors stated that they are starting two randomized trials: One will examine the use of bid treatment with protons to a total dose of 93.6 CGE in 56 fractions with concurrent temozolamide. They intend to run a second trial with the same radiation parameters with concurrent temozolamide and bevacizumab

Clinical/Scientific Implications

The treatment of GBM remains challenging. Outcomes remain poor despite the use of trimodality therapy, even in patients who can be completely resected. The present study addresses the tolerability of the use of hyperfractionated proton therapy in the treatment of GBM. Though this treatment appeared tolerable, it is important to note that the size of the boost area was limited to a relatively small volume. It is also important to note that temozolamide was not used in the present study and there was no adjuvant chemotherapy, which could have affect toxicity.
Given the very small number of patients, it is difficult to make any real conclusion about the outcomes. The majority of patients did have residual disease, and hence it may be that these results do look favorable compared with prior studies, but this is largely speculation.
The finding that caution should be used when interpreting early MRI changes confirms results from prior studies. Caution should be used, with serial imaging prior to discontinuation of chemotherapy or further surgery in patients who have an increase in enhancement on follow up MRI. Nonetheless, the presence of tumor stem cells, though they do not appear viable, is concerning and may suggest that even with these higher radiation doses, there is residual microscopic disease which may remain viable.
Further studies are needed to validate the use of temozolamide in proton therapy, as well as the use of MGMT status and previously published nomograms in patients treated with protons.