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.

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

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

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

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

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.

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

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.

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

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

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

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.

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

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.

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

Results – the pilot study 25 patients treated With tumours ranging from 0.42 -4 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

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

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

Cosmetic Results Satisfaction index (observed/expected) Mean 95% CI Appearance 1.2 (1.1-1.4) Texture 1.2 (1.0-1.4) 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.

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

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.

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 2001. 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.

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

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!

Site of Local Recurrence after BCT Author n %in index q. Clark RM, 1982 680 96% Schnidt SJ, 1984 231 83% Boyages J, 1990 783 81% Kurtz, JM, 1990 1593 86% Fisher B, 1992 1843 100% Veronesi U, 1993 570 90% TOTAL 5770 91%

The Christie Hospital Trial GG Ribeiro, B Magee, R Swindell, M Harris and SS Banerjee Clin Oncol (R Coll Radiol) 1993;5:278-283 708 patients randomised a) Limited Field (LF): 4 Gy (10 days) 8x6 cm area 10MeV to a depth of 2.5cm b) Wide Field (WF): 4 Gy (21 days) whole breast, axilla & scf

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%