# Presentation: 055784

## Workshop on Advanced Technologies in Radiation Oncology

**Minesh Mehta**

## Principal “Dose-Limiting Toxicity”Brain Tumors

**Necrosis rates of ~5% starting at 60 Gy.**
**72 Gy with altered fractionation**
**Visual damage of ~1-3% starting at >54 Gy.**
**Endocrine damage starts at ~45 Gy.**
**Neurocognitive damage:**
**Depends on what you measure, when, & age**
**Cochlear dysfunction starts at >50 Gy**

## Evidence Levels 

**Logically, few of the toxicity data come from phase III trials with toxicity endpoints.**
**Most come from phase I trials, or “institutional experiences”**
**Numerous variables need to be teased out separately, e.g., age, volume, fractionation, comorbidities, other therapies, etc.**

## An example of a phase III trial: RTOG 9006: 60 vs. 72 Gy for GBM

## Further Dose Escalation: Necrosis

- CCG BSG Trials went upto 78 Gy (1 Gy bid)
- U Mich 3 D Trials went upto 90 Gy with reduced volumes
- Recent RTOG 3D dose-escalation trial (9803):
- PTV2 < 75 cc: escalated to 84 Gy (n = 95)
- PTV2 > 75 cc: escalated to 84 Gy (n = 109)

| Group | Level | n | % RT Necrosis (95% CI) |
| --- | --- | --- | --- |
| Group 1 | 66 Gy | 19 | 5.0%  (0, 15.3%) |
|  | 72 Gy | 20 | 10.0%  (0, 23.1%)
 |
|  | 78 Gy | 24 | 8.3%  (0, 19.4%)
 |
|  | 84 Gy | 15 | 6.7%  (0, 19.3%) |
| Group 2 | 66 Gy | 29 |  |
|  | 72 Gy | 18 |  |
|  | 78 Gy | 32 | 6.2%  (0, 14.6%) |
|  | 84 Gy | 10 |  |

- * Toxicity not graded:  found from central review
- †  Number of patients with late toxicity data

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## An Example: Risk of Dementia with WBRT for Brain Metastases

- Retrospective study of 47 patients one-year survivors treated at MSKCC
- 5/47 (11%) patients treated with WBRT developed severe dementia:
- 		6 Gy x 3, 4 Gy x 3
- 		5 Gy x 3, 3 Gy x 5
- 		5 Gy x 3, 3 Gy x 4
- 		6 Gy x 3, 4 Gy x 3 + adria analog
- 		3 Gy x 10 + radiosensitizer
- 0f 15 **patients** treated with _<_3 Gy/fx, 0 had dementia

**DeAngelis LM, et.al. *****Neurosurgery***** 1989;24:798-805.**

**Dementia associated with high-dose fractions.**

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## Can SRS or SRT reduce toxicities?

- Few direct comparisons exist
- Significant dose-escalation can be achieved
- In general, necrosis rates remain under 5%
- However, only small volumes are generally treated
- For long-term toxicity, benign tumors need to be studied and these are generally not included on any clinical trials, e.g. meningioma, vestibular schwannoma, etc.

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## RTOG 90-05: Phase I SRS trial

- 156 patients with rec CNS tumors < 40 mm diameter
- SRS dose by size
- For < 20 mm tumors, dose not escalated > 24 Gy

| Size  | Dose | n | Grade | 3, 4, 5 | CNS tox |
| --- | --- | --- | --- | --- | --- |
| mm | Gy |  | Acute | Chronic | Total % |
| 
 20 | 18
21
24 | 12
18
10 | 0
0
0 | 0
6
10 | 0
6
10 |
| 
21-30 | 15
18
21
24 | 15
15
13
12 | 7
0
7
33 | 7
20
31
8 | 14
20
38
41 |
| 
31-40 | 12
15
18 | 21
22
18 | 5
0
17 | 5
14
28 | 10
14
45 |

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## An example of a phase III trial: RTOG 9305: SRS boost for GBM

- 60 Gy + BCNU +/- SRS boost (15-24 Gy)
- 186 analyzable patients
- 4 vs 0 G3 late neuro toxicity in SRS arm
- QOL comparable (Spitzer)
- MMSE comparable
- Quality-adjusted survival comparable

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## RTOG 9508: QOL, Toxicity

| Trait | WBRT | +RS | p |
| --- | --- | --- | --- |
| KPS  @ 3 mo | 33% | 50% | .02 |
| KPS  @ 6 mo | 27% | 43% | .03 |
| Tumor RR @ 3 mo | 62% | 73% | .04 |
| Edema RR @ 3 mo* | 47% | 70% | .0017 |
| Actuarial LC @ 1 yr | 71% | 82% | .01 |
| CNS death | 31% | 28% | ns |
| G3/4 late tox | < 2% | < 3% | ns |

- * Significantly lower steroid dependence on RS arm

- No difference in outcome by technique, Linac vs. Gamma Knife

## VS Radiosurgery vs FSRT

## Dose, Length & Complications

*Flickinger, IJROBP*

## Probability of Serviceable Hearing

***Probability of Serviceable Hearing***

## Intensity Modulated RT

## Slide 15

## STUDY DESIGN

**Dosimetric comparison of IMRT versus 3DCRT in twenty patients with high-grade glioma.**
** **
**Prescribed Dose: 59.4 Gy, 33 fractions, 4-10 MV **
**Dose constraints for brainstem: 55-60 Gy **
**Dose constraints for optic chiasm & nerves: 50-54 Gy**
**DVHs for target, brain, brainstem and optic nerves/chiasm were generated and compared**
**TCP and NTCP were also calculated and compared**

## COMPARISON OF TARGET AND NORMAL TISSUE DOSIMETRY: 

**COMPARISON OF TARGET AND NORMAL TISSUE DOSIMETRY: **
**IMRT v. 3DCRT**

## So, Can IMRT further reduce toxicities?

- Almost no direct comparisons exist
- Significantly improved DVHs can be achieved
- These may be meaningful for sites such as the chiasm, pit gland, hypothalamus, hippocampus, etc.
- Limited data support that cochlear sparing in the pediatric population might preserve hearing

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## Subventricular zone stem cell compartment
Remains mitotically active in adulthood
Cells have self-renewal capacity
and differentiate into neurons or glia which
can migrate over long distances in the brain
and are involved in repair processes after brain injury/toxicity
In young rats, irradiation with 2 Gy produces apoptosis in the subependymal cell layer and also in the proliferating cellsin the hippocampus
which leads to prolonged impairment of repopulative capacity

**Remains mitotically active in adulthood**
**Cells have self-renewal capacity**
**and differentiate into neurons or glia which**
**can migrate over long distances in the brain**
**and are involved in repair processes after brain injury/toxicity**
**In young rats, irradiation with 2 Gy produces apoptosis in the subependymal cell layer and also in the proliferating cellsin the hippocampus**
**which leads to prolonged impairment of repopulative capacity**

**Compartmental Studies: Stem Cells**

- Doetsch, 1999; Hopewell, 1972; Bellinzona, 1996; Peissner, 1999; Tada, 1999

## 
Many patients exhibit learning/memory deficits with no pathologic changes, especially when the RT field involves the temporal lobes. 
Recent work has shown that hippocampus-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny. 
The hippocampal granule cell layer undergoes continuous renewal and restructuring by the addition of new neurons. 
Radiation at low doses affects the highly proliferative progenitors.  A single low dose to the cranium of a mature rat is sufficient to ablate hippocampal neurogenesis.

**Many patients exhibit learning/memory deficits with no pathologic changes, especially when the RT field involves the temporal lobes. **
**Recent work has shown that hippocampus-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny. **
**The hippocampal granule cell layer undergoes continuous renewal and restructuring by the addition of new neurons. **
**Radiation at low doses affects the highly proliferative progenitors.  A single low dose to the cranium of a mature rat is sufficient to ablate hippocampal neurogenesis.**

**The Role of the Hippocampus**

- _[Monje ML](http://gateway.ut.ovid.com.ezproxy.library.wisc.edu/gw1/ovidweb.cgi?S=IDNJHKIDGACHHO00D&Search+Link=%22Monje+ML%22.au.)__:_** Radiation** injury and neurogenesis. Current Opinion in Neurology. 16:129-34, 2003.

## Hippocampus Avoidance Hypothesis

**The hippocampus plays a significant role in RT induced dementia**
**Doses as low as 2 Gy cause significant toxicity to the hippocampus**
**Conformal avoidance of the hippocampus may help reduce neurocognitive deficits**

## Hippocampus Delineation by Software

## Hippocampus Avoidance with IMRT

- 30 Gy
- 6 Gy
- 3 GY

**Avoidance Region**

**IMRT with tomotherapy**
**achieves significant dose**
**reduction (hippocampus), **
**while delivering 30 Gy to **
**the rest of the brain**

## Can IGRT further reduce toxicities?

- Even in the head, positioning is a significant issue
- IGRT reveals this dramatically
- Application of IGRT might permit more accurate dose delivery
- H/N serves as a good surrogate for the brain in this regard

**Notes:**
Abbreviations:
fx = fractions
Gy = gray
MSKCC = Memorial Sloan-Kettering Cancer Center
WBRT = whole brain radiation therapy

Reference:
DeAngelis LM, Mandell LR, Thaler HT. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery. 1989;24:798-805. 

## Study Design

**Twenty patients analyzed**
**10 conventional patients**
**Prospectively enrolled**
**Daily measurements (6 degrees of freedom) with optically guided patient localization system**
**10 IMRT patients**
**Plans analyzed and selected analysis of impact daily set-up variation**

## Mean Set-up Error (SD)

**Mean Vector:**_** 6.97 mm**_

## 6.97 mm shift- Optic Chiasm

## Paranasal Sinus – Daily Offset

## CNS Tumors with a role for Radiotherapy

## Roles of Radiotherapy

- Post-op adjunct to:
** ****decrease local failure**
** ****delay progression/relapse**
** ****prolong survival, eg GBM, AA**
- Primary curative therapy:
** ****PNET, Germ Cell Tumors,  Pilocytic astrocytoma**
- To halt tumor growth:
-  **Meningioma, Schwannoma**
- To alter endocrine function
- To palliate

## Radiotherapy Improves Survival

## Radiotherapy improves Local Control

***Craniopharyngioma as a case-study: 34 literature reports***

## Radiotherapy diminishes Local Failure

***Meningioma as a case-study: Literature reports***

## The Impact of Radiation Dose

***Medulloblastoma as a case-study: Literature reports***

***Decreasing posterior fossa dose increases relapses***

## The Impact of Radiation Dose

**2 -ve Ph III trials**
**CCG 923: 36 (#44) vs. 23.4 (#45) Gy CSI.**
**3 yr isolated neuraxis failure: 2/44 vs. 11/45.**
**SIOP II: 4 arms; 35 vs. 25 Gy CSI +/- pre-RT chemo**
**5 yr RFS= 75 vs. 42% for chemo RT arms **

***Medulloblastoma as a case-study: Clinical Trials***

***Decreasing CSI dose increases relapses***

## GBM: Dose Escalation

## RTOG 9305: GBM RS Ph III trial

**203 patients with GBM**
**60 Gy + BCNU +/- RS boost (15-24 Gy)**
**Median f/u 44 months**
**MS: 14.1 vs 13.7 months**
**2 yr survival: 22 vs 18%**
**3 yr survival: 16 vs 8%**
**General QOL & cognitive function comparable**

- Souhami, ASTRO 2002

**RADIOSURGERY NOT PROVEN TO PROLONG SURVIVAL IN GBM**

## Technologies for dose-escalation

**Technologies for dose-escalation**

- 5 field Fractionated Stereotactic
- Radiotherapy Technique
**Phase II RTOG trial: RTOG 0023**

## RTOG 0023: Results

- Cardinale, Red J, 2006

**FSRT MIGHT BENEFIT GROSS-TOTALLY RESECTED GBM**

- Although overall survival
- was not improved, there
- was a trend toward improved
- survival with FSRT for
- patients with total resection

## RTOG 9508 Phase III Single Brain Mets: Survival

**RT + SRS (Median survival = 6.5 mo)**

**RT alone (Median survival = 4.9 mo)**

***P*****=0.0470**

**100**

**80**

**60**

**40**

**20**

**0**

**0**

**6**

**12**

**18**

**24**

**Months**

**Percent alive**

- SRS = stereotactic radiosurgery.

## Infiltrative Margins

- Mets

- GBM

## MRSI for Treatment Planning

**34 pts (22 G3, 12 G4) evaluated with MRI/MRSI**
**MRI contours:T2 for initial field; T1 for boost**
**MRSI: Multivoxel technique: CNI (Choline/NAA Index)**
**Results: ****MRSI would change fields**
*T2 estimated microscopic region 50% larger than MRSI*
*T2 missed MRSI abnormality in 88% of pts (upto 28 mm)*
**T1 suggested lesser volume than MRSI**
**T1 suggested different location than MRSI**

*Pirzkall A: IJROBP 2001*

*McKnight: J Neurosurg, 2002: 90% sensitivity & 86% biopsy specificity for CNI >2.5*

## Conclusions

**Radiotherapy plays a major role in the management of most primary brain tumors**
**Local failure is still paramount**
**Failed strategies: limited dose escalation, neutrons, brachytherapy, Imidazoles & BUdR**
**Newer technologies may allow an improved therapeutic index**