1. Cryotherapy for a spectrum of breast cancer: US and CT-guidance. Peter J. Littrup, M.D. 1* Bassel Jallad, M.D. 1 Priti Chandiwala-Mody, D.O. 2 Monica D’Agostini 1 Barb Adam, N.P. 1 David Bouwman, M.D. 3 1 Karmanos Cancer Institute 2 Department of Radiology, Wayne State University 3 Department of Surgery, Wayne State University * Co- Inventor/Founder: Single Phase Liquid Cooling (SPLC) by CryoMedix, LLC

2. Goals & Hypothesis  To assess the technical feasibility, patient acceptance, imaging and clinical outcomes of percutaneous cryotherapy for breast cancers.  Multiprobe cryoablation for diverse presentations of breast cancer can be monitored to create 1cm visible ice coverage beyond all tumor margins, resulting in thorough cytotoxic coverage.

3. Introduction:  Current treatments for LOCAL Breast Cancer include surgery, radiation and/or chemotherapy  Breast Conservation is the primary research focus for new treatment options.  Cryotherapy works by delivering lethal cold to ANY cell ~ -30 0 C x 2 cycles  Benefits of Cryo? –Much lower pain than heat-based ablations –Easily visualized on CT/US/MR –Excellent Healing ~ Eliminates disfiguring surgery

4. Introduction: Breast Cryotherapy Research: Single probe  Cryotherapy-assisted lumpectomy –Tafra, et al. Ann Surg Oncol. 2003; 10:1018 –1024  Excisional data –Pfleiderer, et al. Invest Radiol. 2005; 40:472-477 –Roubidoux, et al. Imaging: Radiology. 2004; 233:857-867  Conclusions: – 100% kill for all tumors <1 cm & 1-1.5 cm with no DCIS – Unreliable kill for tumors > 1.5 cm – Incomplete along POSTERIOR margins

5. Materials and Methods: Littrup et al., Lethal Isotherms of Cryoablation in a Phantom Study: Effects of Heat Load, Probe Size, and Number JVIR 2009; 20:1343-1351 Cryotherapy for breast cancer: A feasibility study without excision. J Vasc Interv Radiol 2009; 20:1329–1341.  Minimum of 2 probes needed to cover 1cm tumor with lethal ice (< -30°C isotherm)  Multiple probes increase lethal ice: Surface area = 55% - 4 probes, 18% - 1 probe Multiple probes and/orMultiple probes and/or Longer freeze timesLonger freeze times correct for: - higher heat loads - lower probe power

6. Materials & Methods: Patients - Procedures  Informed consent included thorough counseling that cryo was NOT standard of care, esp for newly dx potentially curative  14 patients with 27 cancer foci of newly dx or recurrent breast cancer were treated using US and/or CT-guidance  Saline injections interposed between the developing ice ball and the skin or chest wall for further thermal protection.  Biopsy performed at ice margins immediately after procedure.  CT and MRIs were performed in CA patients at available follow-up times, up to 6 years post-procedure.

7. Materials & Methods: Equipment

8. Results: Locally Advanced Breast Cancer Littrup PJ, et al. JVIR 2009

9. Results: Locally Advanced Breast Cancer Littrup PJ, et al. JVIR 2009

10. Results: Newly Dx Breast Cancer Five-year Littrup PJ, et al. JVIR 2009

11. Results: Locally Advanced BCa & Implants Littrup PJ, et al. JVIR 2009

12. Cryotherapy for BrCA: Local Recurrence Littrup PJ, et al. JVIR 2009 PreImmediate 1 mo. 18 mo.

13. Results: Patient  Clinical difference – no resection!  14 patients: –7 Locally advanced – on chemo/hormonal tx  One had implants – froze into without damage –7 Intent to cure – multifocal + XRT/hormonal  Total tumors – 27  Average tumor size – 1.7+ 1.2 cm (range: 0.5-5.8)  Minimal distortion – 80-90% resorption 6-12 mo.  No localized recurrences –One regional recurrence in breast/axilla

14. Results: Procedure  Average cryoprobes - 3.2  Average ablation size – 51 mm  MR planning and follow-up crucial  Guidance – 8/14 pts CT and US; 6/14 US only  US/CT-guidance superb - operator dependent  No complications  Minimal discomfort - entirely outpatient  Able to address axillary nodes – nerves

15. Future of Breast Cryotherapy: MR-compatibility Single Phase Liquid Cooling (SPLC)* *CryoMedix, LLC

16. Vascular/Endoscopic 10 Sec 20 Sec 1 Min 2 Min 20 Thaw

17. MR - Compatibility MR-monitored breast CA: Cadaver Sagittal (left) and axial views of MR-compatible 1.5 mm cryoprobes at ~1.2mm apart, generating immediate "cold" ice with minimal signal which then thaws over time (right), (sharp initial margins, as well as greater T2 signal with thawing at 15 minutes).

18. Conclusions  Ensure cytotoxic coverage - multiple probes  Minimal pain  Cosmetic satisfaction – implants OK, breast conservation method  Locally curative, control disease process  Future: FDA trial with more patients and use of new MRI compatible cryotechnology (operator independence) is being planned

19. Thank You!