Clinical Studies - Cyberknife

Principal Investigator: Dr Siddhartha Ghosh*

Co-Principal Investigator: Dr Debnarayan Dutta*

*Apollo Speciality Hospital, Chennai

Title: Prospective assessment of activities of daily living, quality of life and

survival function in good performance status high grade gliomas treated by

conformal radiation therapy followed by boost with Cyberknife

Why this study

- All dose escalation studies were done in pre-TMZ era

- Role of dose escalation with better imaging, lesser margin and TMZ

needs to be evaluated.

- CyberKnife will provide lesser margin & higher dose to contrast

enhancing mass after conformal radiation therapy

- Higher dose may improve survival without additional toxicity

•Poor prognosis HGG pts will be accrued after screening.

•Pts will be accrued in 12 months and duration of the study is maximum 3 years.

•Pts willing for the study will undergo Modified Barthel’s test, quality of life questionnaire and clinical evaluation

prior to radiation therapy treatment and at subsequent follow ups.

•All pts will be treated with maximal safe resection followed by adjuvant radiation therapy with intensity modulated

radiation therapy (3DCRT; 50 Gy/25 fr/5wk) followed by boost to the contrast enhancing areas with Cyberknife

(20 Gy/5 fr/1 week).

•Treatment will be started after recovery from the surgery. GTV is contrast enhancing region on MRI scan. CTV is

1.5-2 cm margin. PTV margin will be 5 mm. Appropriate supportive care (steroids, anticonvulsants).

•Cyberknife boost will be started within one week of completion of IMRT. Target will be contrast enhancing region

on MRI scan. Perfusion scan, MR spectroscopy will guide in the target contouring. Patient will continue TMZ till

completion of radiation (including Cyberknife).

•Concomitant chemotherapy (Temozolomide; 75 mg/m2 D1-42) will be given along with radiation.

•Adjuvant TMZ will be started 4 week after completion of RT (200 mg/m2; D1-5, 4 weekly for 6 cycles).

•Analysis will be done with respect to survival function, ADL and QOL scores. Cost effective analysis will be done.

Methodology

Title: Prospective assessment of ADL, QOL & survival function in good

performance status HGGs treated by 3DCRT followed by boost with CK

Eligibility Criteria

- Histopathologically confirmed high grade gliomas (GBM).

- Karnosky performance status >70.

- Willing for IMRT and Cyberknife treatment.

Ineligibility criteria

- Age > 65 yrs.

- Previous radiation or surgery treatment for brain disease.

- Patient not expected to complete planned treatment.

Inclusion criteria for screening in the trial



Answer must be [yes]

•High graded glioma: [Yes] / [No]

•Willing for 3DCRT and Cyberknife treatment: [Yes] / [No]

•Suitable to complete planned treatment with surgery and radiation: [Yes] / [No]

Answer must be [No]

•Age >65 yrs: [Yes] / [No]

•Prior radiation or surgery treatment for brain disease: [Yes] / [No]

Primary aim:

1. To evaluate survival functions (progression free and overall survival) after

higher radiation dose with conformal RT and Cyberknife boost.

Secondary aim:

1. To evaluate quality of life (QOL) and activities of daily living (ADL)

after higher dosage of radiation therapy and at subsequent follow up.



Radiation schedule

Conformal RT : CTV: Pre-operative volume (T1 contrast and including T2 hyperintense)

PTV: 0.5 cm margin

Dose schedule: 50 Gy/25 fr/5 wk, 5 days/wk

PTV coverage with 95% isodose.

93% isodose coverage >99% PTV volume.

Cyberknife Boost: CTV: Post-IMRT contrast enhancing residual disease

No CTV or PTV margin

Additional information from perfussion scan may be taken.

In that situation, apart from contrast enhancing region hyperperfused

region will also be included in GTV.

Dose schedule: 20 Gy/5 fr/1 wk

Conc TMZ 75 mg/m2 & Adj TMZ 200 mg/m2



Assessments

• Toxicity assessment CTCAE V3 toxicity assessment criteria

• Activities of daily living: Modified Barthel’s Index (BI)

• Quality of life: EORTC QLQ C30 & BN 20 (Hindi and English)

• Survival functions



Assessments

Assessment Pre-RT 4 week

post RT

3 mo

post-RT

6 mo

post RT

9 mo

post RT

12 mo

post-RT

@ 3

monthly

Till 3 yrs

Clinical evaluation √ √ √ √ √ √ √

CTCAE v3 √ √ √ √ √ √ √

Blood examination (CBC) √ √ √ √ √ √ √

MRI Scan* × √ × √ × × ×

Modified Barthel’s √ √ √ √ √ √ √

EORTC QLQ C30 & BN20 √ √ √ √ √ √ √



Patient required: 25 patients

Duration of the study: Accrual in twelve months and follow up for 3 years.

Statistical analysis: Survival function improvement if any after higher radiation dose

will be evaluated one year after accrual of 25 patients or at 3 year after initiation of the

study. Neurological function and QOL will also be evaluated.Total duration of hospital visit

in days with respect to overall survival will be analyzed.

Discontinuation of study: Study will be discontinued if 1) poor patient

accrual (<10 patients in 2 years), 2) High incidence of acute toxicity (>50% patient

requiring admission related to radiation induced events), 3) high mortality rate ( first 5

patient assessment, if median survival <6 months)



References

1. Thilmann C, Zabel A, Grosser KH, et al. Intensity-modulated radiotherapy with an integrated boost to

the macroscopic tumor volume in the treatment of high-grade glioma. Int J Cancer. 2001 ;96(6):341-

9.

2. Jones B, Sanghera P. Estimation of radiobiologic parameters and equivalent radiation dose of

cytotoxic chemotherapy in malignant glioma. Int J Radiat Oncol Biol Phys.2007;68(2):441-8.

3. Taphoorn MJ, Stupp R, Coens C, et al. Health-related quality of life in patients with glioblastoma: a

randomised controlled trial. Lancet Oncol. 2005 ;6(12):937-44

4. Brown P, Ballman K, Rummans T, et al. Prospective study of quality of life in adults with newly

diagnosed high-grade gliomas. J Neurooncol76(3);283-91: 2006.

5. Budrukkar A, Jalali R, Dutta D, et al. Prospective Quality of Life assessment using EORTC QLQ 30

and brain cancer module (BN 20) in 257 consecutive adult patients with primary brain tumours in a

typical Neuro-Oncology clinic in India. J Neurooncol 2009 Jun 23 [PMID: 19548070]

6. Brazil L, Thomas R, Laing R et al. Verbally administered Barthel Index as functional assessment in

brain tumour patients. J Neurooncol 34(2); 187-92: 1997.

7. Mahadevan A. A Phase II Study of Hypofractionated Radiation With Cyberknife Stereotactic

Radiosurgery Boost for High Grade Gliomas in Elderly Patients With Good Performance Status

(www.clinicaltrials.gov) [NCT00386919]

References

1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant

temozolomide for glioblastoma. N Engl J Med 2005;352:987-996.

2. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant

temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised

phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-466.

3. Jalali R, Datta D. Prospective analysis of incidence of central nervous system tumours presenting in

a tertiary cancer hospital from India. J Neurooncol 2008:87;111–114.

4. Jalali R, Basu A, Gupta T, et al. Encouraging experience of concomitant Temozolomide with

radiotherapy followed by adjuvant Temozolomide in newly diagnosed glioblastoma multiforme:

single institution experience. Br J Neurosurg 2007; 21:583-87

5. Laperriere NJ, Leung PM, McKenzie S, et al. Randomized study of brachytherapy in the initial

management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys 1998;41:1005-

1011

6. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery

followed by conventional radiotherapy with carmustine to conventional radiotherapy with

carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology

Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60:853-60

7. Selker RG, Shapiro WR, Burger P, et al. The Brain Tumor Cooperative Group NIH Trial 87-01: a

randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial

radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery. 2002 ;51(2):343-55

Study status

Accrual:

Recruiting Patients

For Screening contact

Dr Debnarayan Dutta

Mail: [email protected]

Ph: +91 9884234290

mailto:[email protected]

Healthcare

Clinical Studies - Cyberknife