Clinical decisions in the optimization Clinical decisions in the optimization process process

I. Emphasis on tumor control issuesI. Emphasis on tumor control issues

Avi EisbruchAvi Eisbruch

University of MichiganUniversity of Michigan

Standard radiotherapyStandard radiotherapy

Limited ability to control dose distribution Limited ability to control dose distribution across the treated volumeacross the treated volume

Large body of past experience that Large body of past experience that dictates standard care regarding doses dictates standard care regarding doses prescribed to tumors, dose homogeneity, prescribed to tumors, dose homogeneity, and maximal doses allowed to critical and maximal doses allowed to critical organs.organs.

Optimized intensity modulated Optimized intensity modulated radiotherapyradiotherapy

Vastly improved ability to control dose Vastly improved ability to control dose distributions. distributions.

How should we “optimize” dose How should we “optimize” dose distributions?distributions?– The limiting factor is our knowledge of what is The limiting factor is our knowledge of what is

clinically desired. clinically desired.

Optic nerve damageOptic nerve damage

Following definitive, standard RT of Following definitive, standard RT of paranasal sinus cancer: 21/78 (27%) paranasal sinus cancer: 21/78 (27%) patients had unilateral blindness and 4 patients had unilateral blindness and 4 (5%) had bilateral blindness.(5%) had bilateral blindness.– Katz, Mendenhall, et al. Head Neck 2002.Katz, Mendenhall, et al. Head Neck 2002.

Martel et al, IJROBP 1997

3D conformal RT of paranasal sinus cancer

Optic nerve damage following conformal-3D Optic nerve damage following conformal-3D RT of paranasal sinus cancerRT of paranasal sinus cancer

2 cases of blindness out of 20 patients 2 cases of blindness out of 20 patients treated definitively and were free of treated definitively and were free of disease >2 years.disease >2 years.

Parameters for normal tissue complication Parameters for normal tissue complication probabilities (NTCP) were derived from the probabilities (NTCP) were derived from the dosimetric and the clinical data.dosimetric and the clinical data.

Martel et al, 1997

IMRT of paranasal sinus cancer: IMRT of paranasal sinus cancer: sparing the optic nervessparing the optic nerves

“ralatively easy case”

Tsien, Eisbruch, et al, IJROBP 2003

Paranasal sinus cancer: sparing Paranasal sinus cancer: sparing the optic nervesthe optic nerves

Tsien, Eisbruch, et al, IJROBP 2003

Paranasal sinus cancer: sparing Paranasal sinus cancer: sparing the optic nervesthe optic nerves

This was more difficult !

Tsien, Eisbruch, et al, IJROBP 2003

Paranasal sinus cancer: sparing Paranasal sinus cancer: sparing the optic nervesthe optic nerves

Tsien, Eisbruch, et al, IJROBP 2003

Sparing the optic nerves by IMRTSparing the optic nerves by IMRT

While IMRT provides highly conformal While IMRT provides highly conformal dose distributions, trade-offs between dose distributions, trade-offs between organ sparing and target under-dose do organ sparing and target under-dose do exist. exist.

An intelligent choice between these trade-An intelligent choice between these trade-offs cannot be made unless the offs cannot be made unless the parameters of tumor control and parameters of tumor control and complication probability models are known complication probability models are known with a higher certainty. with a higher certainty.

Tumor control vs. DoseTumor control vs. Dose

The most elusive issue due to the large The most elusive issue due to the large heterogeneity in the density of tumor stem heterogeneity in the density of tumor stem cells and their sensitivity to radiation.cells and their sensitivity to radiation.

The doses we prescribe in order to kill The doses we prescribe in order to kill tumors are dictated by the presumed tumors are dictated by the presumed sensitivity of the adjacent normal tissue, sensitivity of the adjacent normal tissue, rather than by the needs to kill the tumor.rather than by the needs to kill the tumor.

A recent exampleA recent example

Locally advanced cancer of the Locally advanced cancer of the nasopharynxnasopharynxMost of the planning treatment volume for Most of the planning treatment volume for the gross, observed disease was the gross, observed disease was encompassed by the desired dose (70 Gy)encompassed by the desired dose (70 Gy)The parts of the tumor adjacent to the The parts of the tumor adjacent to the brain stem received less than the desired brain stem received less than the desired dose to reduce the risk of a severe dose to reduce the risk of a severe complication.complication.

Assessment of the sites of Assessment of the sites of recurrences relative to the dose recurrences relative to the dose

delivereddelivered

CT at time of RecurrenceCT at time of Recurrence

recurrence volume

Transfer of Recurrence VolumeTransfer of Recurrence Volume

Planning CT

recurrence volume

location

50 Gy

60 Gy

Recurrence DefinitionsRecurrence Definitions

% recurrence volume receiving minimal % recurrence volume receiving minimal intended dose intended dose (70 Gy to GTV, 60 to resection bed (70 Gy to GTV, 60 to resection bed or high-risk CTV, 50 to low-risk CTV):or high-risk CTV, 50 to low-risk CTV):

In fieldIn field 95% 95%

MarginalMarginal 20 - 95%20 - 95%

Outside fieldOutside field 20% 20%

0

20

40

60

80Mean Dose

Dos

e (G

y)

Mean Dose to Recurrence VolumesMean Dose to Recurrence VolumesMean Dose to Recurrence VolumesMean Dose to Recurrence Volumes

Recurrence

0

20

40

60

80D

ose

(Gy)

Minimum Dose to Recurrence Minimum Dose to Recurrence VolumesVolumes

Minimum Dose to Recurrence Minimum Dose to Recurrence VolumesVolumes

Recurrence

Minimum Dose

Rouvière, Anatomy of the Human Lymphatic System, Edwards Bros., 1938

Som et al.,Arch. Otolaryngol.Head Neck Surg.1999

Neck Node Levels

Update: Pattern of failureUpdate: Pattern of failure

160 patients treated with IMRT since 1994160 patients treated with IMRT since 1994

24 local-regional failures24 local-regional failures

20 in-field 20 in-field

All 4 marginal failures can be explained by All 4 marginal failures can be explained by the clinical decisions that had been made the clinical decisions that had been made regarding the targets.regarding the targets.

Most failures are in-fieldMost failures are in-field

Should we escalate the dose?Should we escalate the dose?

Would dose inhomogeneities (“hot spots”) Would dose inhomogeneities (“hot spots”) within the targets help improve tumor within the targets help improve tumor control?control?– Fowler, Deasy: modeling: Over-dosage in part Fowler, Deasy: modeling: Over-dosage in part

of the target may compensate for volumes of of the target may compensate for volumes of underdosage within the target (as long as underdosage within the target (as long as these volumes are not too large)these volumes are not too large)

Xia et al, IJROBP 2000

Over-dosing the GTV

In addition to the nominal In addition to the nominal dose…dose…

““Hot volumes” in a highly nonuniform plan Hot volumes” in a highly nonuniform plan are delivered at a higher dose/fraction are delivered at a higher dose/fraction than the prescribed dose. than the prescribed dose.

The biologically equivalent dose in the hot The biologically equivalent dose in the hot volume is higher than the DVH impliesvolume is higher than the DVH implies– 80 Gy over 35 treatments: 2.3 Gy/fraction, 80 Gy over 35 treatments: 2.3 Gy/fraction,

NTD=85 Gy. NTD=85 Gy.

Where are the “hot spots” locatedWhere are the “hot spots” located

Change in Target Homogeneity

0

20

40

60

80

100

0 20 40 60 80Dose (Gy)

% V

olu

me

00111ep P2

PTV66ContraParotid

+/-5%

+/-20%

+/-10%

Vineberg et al.

Tumor Control Probability vs. Treatment Delivery Time

JZ Wang et al, IJROBP 2003

Should limiting treatment time be Should limiting treatment time be incorporated into the treatment incorporated into the treatment

optimization process?optimization process?

Interim conclusionsInterim conclusions

The pattern of recurrence in our and other The pattern of recurrence in our and other series suggests that dose escalation to all series suggests that dose escalation to all or parts of the targets at highest risk of or parts of the targets at highest risk of failure may improve tumor control. failure may improve tumor control.

This is supported by models of tumor This is supported by models of tumor control probability (TCP)control probability (TCP)

Clinical validation is still lacking. Clinical validation is still lacking.