1. TARGeted Intra-operative radioTherapy (TARGIT)
for breast cancer - a randomised trial
Jayant Vaidya, Michael Baum, Jeff Tobias, Joan Houghton,Mo Keshtgar, Irving Taylor, Richard Sainsbury, Derek D’Souza, S Morgan, M Metaxas, K Harte, A Sliski, E Thomson
Good afternoon ladies and gentlemen; today I shall be talking about TARGeted intraoperative radiotherapy, in short TARGIT.

2. Local treatment of breast cancer
Have the principles really changed?
Halsted’s Radical Mastectomy
Limited Surgery plus Radical Radiotherapy

3. Are there any problems with current approach?
Radiotherapy typically takes 6wks to deliver
Patients don’t like these 30 daily visits
Geography prevents many women from receiving conservative breast surgery
Breast cancer = 1/3rd of RT work-load
Long waiting lists in many centres
Are there any problems with the current approach? Radiotherapy typically takes six weeks to deliver. Nobody likes these 30 daily Hospital visits. In addition, geography prevents many of the men from receiving best concerning surgery in many parts of the word such as Australian outback, rural America and India. breast cancer constitutes 1/3 of workload of credit that the unit’s word wide and this least two long waiting lists in many centers

4. The Solution
A novel radiotherapy technique that will accurately deliver all the necessary radiotherapy in ONE sitting
Treat only the index quadrant of breast
A solution to these problems can be a novel radioTherapy technique that can’t accurately deliver all the necessary radioTherapy in one sitting and we treat only the index quadrant of the breast

5. The Rationale *Vaidya et al, Br. J. Cancer; 1996
Whole organ analysis of
mastectomy specimens*
3-D analysis
63% harbour occult cancer
80% of these are in other quadrants
The rationale for treating only the index quadrant comes from: an analysis of mastectomy specimens. 63% of these specimens are found to have harbour occult tumours. And when analyzed in three dimensions we find that 80 percent of these are in other quadrants
*Vaidya et al, Br. J. Cancer; 1996

6. The Rationale but, in trials of conservative surgery:
>90% recurrences occur in the index quadrant
- whether radiotherapy is given or not
The occult cancers in other quadrants of the breast are probably not the cause of local recurrence.
Radiation to the index quadrant alone might be sufficient
In contrast, more than 90% of local recurrences in breast conserving trials occur in the index quadrant. This is true even if radiotherapy is not given. Therefore, occult cancers in other quadrants are probably not the cause of local recurrence and radiotherapy to the index quadrant alone might be sufficient.

7. Targeted Intra-operative Radiotherapy: (Targit) A Novel Approach
Targeted intraoperative radiotherapy – is a novel approach based on

8. The Technique PRS400 (Intrabeam)
Novel technology. Intrabeam is a miniature electron generator and accelerator- click-. That accelerates electrons along –click- this 3.2 mm tube. They strike the tip to generate soft x-rays which a modulated by the applicator to give a uniform field of radiotherapy delivered from within the breast in a routine operation theatre
PRS400 (Intrabeam)
A miniature electron generator and accelerator
Accurately delivers radiotherapy from within the breast in about 25 minutes.

9. Physical radiation dose
Soft X-rays
Small ‘very-high-dose’ region
Quick attenuation (1/r3)-
distance protects normal tissues
Shielding is easy
20 Gy at 2mm
Because they are soft x-rays, there is a small very high dose region and a quick attenuation of the dose, which protects normal tissues. The physical dose at the applicator surface is 20Gy which reduces to 1 Gy at 27mm
Physical radiation dose
1 Gy at 27mm

10. So after wide local excision, the applicator, which comes in various sizes, is placed in the tumour bed.

11. Applicator is inserted and purse string is tied
A purse string through the breast tissues apposes the target tissues to the applicator surface allowing true conformal radiotherapy.
Applicator is inserted and purse string is tied

12. the target - the pliable breast tissue - is conformed to the source
Rather than the complicated conformation of the source to the target...
the target - the pliable breast tissue -
is conformed to the source
The beauty of this technique is that instead of the complicated and uncertain conformation of the source to the targit, the pliable breast tissue – the target – conforms to the source, allowing true conformal radiotherapy.

13. Estimated Biologically equivalent radiation dose (BED)
External
Boost
Targit
with PRS
Distance from applicator
/=10
/=1.5
2mm e.g. breast
12 Gy
53 Gy
121 Gy
The superior dosimetry of the technique means that the targit tissues get a much higher biologically effecetive dose of radiation and the overlying skin or normal tissues receive a much lower dose.
10mm e.g. skin
12 Gy
7 Gy
21 Gy

14. To test the the TARGIT technique -its feasibility and safety
2. To test the approach
of treating only the index quadrant
In our study, we first tested the feasibility and safety of the new technique and are now in the process of testing the novel approach of treating only the index quadrant.

15. Phase I/II study July 1998-Jan 2000
Early operable breast cancer: <4cm in size
Wide Local excision + axillary surgery
Boost radiation with Photon Radio Surgery (PRS) intra-operatively
in our pilot study, we treated patients with early operable breast cancers with wide local excision and axillary surgery followed immediately by the Intrabeam radiotherapy which substituted the routine postoperative boost.
Whole breast radiotherapy post-op

16. Results – the pilot study
25 patients treated
With tumours ranging from cm
Median follow up 30 m
No major complications
No recurrences
We treated 25 patients with tumours ranging from .42 to 4cm. The median follow up is 29 months. And … touch wood… we have had no major complications and there have been no recurrences. The cosmetic results are excellent.
Cosmetic results are good

17. Complications
Our 3rd patient had radionecrosis of skin near the scar- skin was too close to the applicator
9 months
Our third patient’s skin was pulled too close to the applicator by the purse string suture. She presented at 3 months with this scabbing - which resulted in a wound that healed by secondary intention. Fortunately, the cosmetic results at 9 months and 28 months are satisfactory.
28 months

18. Cosmetic Results Photographs
Patient’s own assessment of the cosmetic result – appearance and texture:
What would be your expected score (out of 10)?
What is the actual score (out of 10)
Satisfaction index = Actual / Expected
We assessed cosmetic result by photographs and with patient satisfaction index- which is calculated by dividing a score out of 10 of the actual appearance or texture by the expected appearance or texture

19. Cosmetic Results Satisfaction index (observed/expected) Mean 95% CI
Appearance ( )
Texture ( )
In only 4 out of the 25 patients in the pilot study, was the observed less than expected.
The satisfaction index averaged at 1.2 for both the appearance and texture and only 4 patients’ actual scores were less than their expected scores.

20. We submitted the protocol for the randomised trial to our ethics committee and the Lancet, who published it on their website.

21. Breast cancer - breast conserving therapy
Randomisation
Study Arm
Control Arm
Wide local excision of primary tumour +
SNB/ axillary dissection +
Targeted Intraoperative Radiotherapy
(If histopathology is Lobular or EIC, add 5wks of postoperative radiotherapy)
Wide local excision of primary tumour +
SNB/ axillary dissection +
6 wks of Postoperative Radiotherapy
Patients undergoing conservative breast surgery are being randomised to receive either TARGIT or the usual 6 wks of postoperative radiotherapy. Patients with lobular cancers are either excluded or, if determined postoperatively, are given 5 wks of postoperative radiotherapy.

22. 1st patient randomised on 29 March 2000
- 29 patients randomised until June 2001
No complications in the IORT arm
1 wound infection in the post-op RT arm
Median follow up is 15 months
Cosmetic appearance is good
No recurrences to date
Our 1st patient was randomised on 29 of March 2000 and we have randomised 29 patients until June There have been no complications in the Targit arm; there was one wound infection in the postoperative arm, and at the median follow up of 15 months, the cosmetic appearance is good and there is no local recurrence.

23. Save up to 1/3rd of the workload of radiotherapy units world-wide
If proven, Targit could
Save up to 1/3rd of the workload of radiotherapy units world-wide
Allow women from remote areas to avail of breast conserving therapy
If proven, Targit could save up to 1/3rd of workload of radiotherapy units worldwide and allow women from remote areas to avail of breast conserving therapy

24. The cost of delivering Targit is about half that of a 6 week course of radiotherapy
Assuming that 60% of patients have conservative therapy, it could save £15,500,000 pa in the UK
Worldwide, it could save thousand of women from losing their breasts!

25. Site of Local Recurrence after BCT
Author n %in index q.
Clark RM, %
Schnidt SJ, %
Boyages J, %
Kurtz, JM, %
Fisher B, %
Veronesi U, %
TOTAL %

26. The Christie Hospital Trial
GG Ribeiro, B Magee, R Swindell, M Harris and SS Banerjee Clin Oncol (R Coll Radiol) 1993;5:
708 patients randomised
a) Limited Field (LF):
4 Gy (10 days) 8x6 cm area MeV to a depth of 2.5cm
b) Wide Field (WF):
4 Gy (21 days) whole breast, axilla & scf

27. The Christie Hospital Trial 8 Year Results
Breast Recurrence: LF WF
Duct Carcinoma (n=534) 15% 11%
EIC (<25% invasive, (n=45) 21% 14%
Lobular Carcinoma (n=95) 34% 8%