Radiofrequency ablation of primary breast cancer Rache M. Simmons, MD, FACS, Associate Professor of Surgery, Strang Weill-Cornell Breast Center, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY

Radiofrequency Ablation		Radiofrequency Ablation
• Established as effective treatment of metastatic hepatic tumors • Experimental for treatment of lung, bone, brain, kidney, prostate tumors • Current protocol for treatment of breast cancers radiofrequency interstitial tissue ablation		• Destruction of solid tumors through application of high frequency alternating current • Electrode itself is not the source of heat • Frictional heat from ions within tissue changing direction with alternating current
RF Breast Cancer Protocol		RF Breast Cancer Protocol
• 15 g hollow needle probe • Multiple electrodes form a star-like destructon • Temperature sensing probes for feedback to assess target temperature		• 5-7 minute to reach target temperature of 95oC (cell death at 50oC) • 15 minutes at target • 1 minute cool down
RF Breast Cancer Protocol		RF Breast Cancer Control
• Tri-institutional Trial (NYPH, MD Anderson, John Wayne) • Ablate and reset to confirm tumor destruction		• Tumor 2 cm or less in diameter • Tumor sonographically detectable • Distance of 5mm from the chest wall and overlying skin • Preoperative core biopsy diagnosis of invasive carcinoma and determination of ER/PR
RF Breast Cancer Protocol		RF Breast Cancer Protocol
• At time of breast cancer surgical treatment • Sedation or general anesthesia • Sentinel node biopsy (+/- axillary dissection), BMA • Ablative procedure • Followed by standard lumpectomy or mastectomy		• Pathological Analysis • Standard H&E • NADH tumor viability stain • Viable cell stain blue (cytoplasmic granules with NADH oxidation reaction) • Non-viable cells no stain
Conclusions		Conclusions
• RF offers an exciting potential treatment for selected breast cancers • More data is needed to revise patient selection		Proposed next phase of protocol: • Ablation with leaving tumor in vivo 306 months prior to resection • Proceed with adjuvant therapy • Monitor potential enhanced immunologic response to tumor • Follow probably involution of tumor

Laser Photocoagulation of Breast Cancer Using MRI Steven E. Harms, MD, FACR, Professor of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, and Medical Director, Aurora Imaging Technology, North Andover, MA

Introduction

Breast conservation surgery was developed to reduce the disfigurement of mastectomy while providing an equivalent therapeutic outcome.2,3,4,12,50,62 Most women now prefer lumpectomy to mastectomy surgery, despite the increased cost and need for radiation therapy. These factors indicate the value our society places on improved cosmesis. Small breast cancers (< 1 cm) have an excellent prognosis, with a disease-free survival at 20 years approaching 90%.27,33,37,38,48,56 These outstanding results were derived from long term follow-up studies where breast conservation was not yet available. Since these patients were treated with mastectomy, it is clear retrospectively that they achieved little therapeutic gain from the loss of their breast.

Following the philosophy of breast conservation therapy, the obvious next step is to apply modern minimally invasive methods to achieve an even greater cosmetic benefit. Minimally-invasive therapy has been applied for a variety of solid tumors in other organs including liver, brain, prostate, lung, pancreas, and uterus.1,6,32,39,40,43,51,60,61 These methods effectively destroy tissue, and the application for the destruction of breast tumors is straightforward19,20,25,26,42,47.

Despite the potential importance of minimally invasive therapy in the breast, its application has been more cautious than in other systems. There are several reasons for concern on the part of research teams in this area. The use of minimally invasive therapy in most current applications involves palliation of disease where the therapeutic alternatives incur more risk or are not available. For example, the treatment of colorectal metastases to the liver can improve an otherwise dismal prognosis. There is little downside risk to undergoing the minimal-risk procedure. The alternative to the treatment of liver metastases is surgery, where the risk of death is significant.

The use of minimally invasive therapy for breast cancer, however, is considered in a completely different clinical picture. Patients with small breast cancers that are applicable to minimally invasive therapy already have an outstanding prognosis. If the treatment fails, they may have lost their best chance for curing a clearly treatable disease. These ethical concerns will be some of the greatest challenges in the development of clinical trials for minimally invasive therapy in the breast.

This chapter will outline the integration of breast MRI and minimally- invasive therapy for breast tumors, considering the various technical obstacles that are typically encountered.

How do we know if we are treating all of the disease?

It is well known that subclinical residual disease is present after lumpectomy surgery. A number of rigorous pathologic studies using serial sectioning of mastectomy specimens have documented the occurrence of otherwise unsuspected foci of disease in about 40% of breasts. 30,35,55 In addition, the NSABP B-06 trial determined that a similar percentage of cancers would recur if radiation therapy was not given. These findings are the justification for the routine use of radiation following lumpectomy surgery.12 It is clear that radiation will be needed in patients treated with minimally invasive therapy. More importantly, the therapeutic benefit of radiation is only achieved when the pathologic margins of the lumpectomy are clear of residual tumor.15,46,49,52,54,59

Validation of clear pathologic margins will not be possible when minimally- invasive therapy is employed. This would not be an issue if we knew that our imaging methods were accurate in the definition of tumor margins. Unfortunately, clinical trials have proven the traditional methods for predicting margins are very inaccurate. About half of lumpectomy surgeries can be expected to reveal positive margins upon pathologic analysis.15,46,49,52,54,59 One Japanese study determined that 90% of simulated lumpectomies would result in residual tumor.17 Due to the high incidence of positive pathologic margins, we need a greater certainty of a potential for clear margins than is currently available from conventional imaging methods.

Can MRI be used to reliably determine clear treatment margins? If we no longer have pathology to determine adequate lumpectomy margins, we will need imaging guidance that will be equivalent to the accuracy of pathology. Most published MRI series have not been validated with this feature in mind. The objective for most MRI studies was to determine the benign from malignant.28,44 Areas of the breast that are thought to be negative by imaging are not systematically sampled. This design leads to an under-reporting of false negatives. There has been little effort directed toward the validation of MRI as a method to achieve clear pathologic margins. Therefore, the direct application of most MRI methods for minimally invasive therapy of breast neoplasms is not straightforward. The need for accurate margin determination was a major incentive for the validation of RODEO (Rotating Delivery of Excitation Off-resonance) as a staging method for breast cancer. This analysis was performed by systematically correlating RODEO images with serial sectioned mastectomy specimens. The specimen sectioning followed previous pathologic studies where the breast was sliced at 5 mm intervals, mapped by the pathologist, and correlated with the MRI findings. This approach allowed the accurate evaluation of lesion sizes and margins and provided potential for determining the prevalence of false negatives. 8,21,22,23,24

DCIS is commonly encountered and is important in the management of breast cancer. Pure DCIS may represent up to one third of cancers in some unique circumstances that must be considered for breast lesion therapy. Many of these therapies have been applied to the treatment a screened population and commonly accompanies infiltrating cancer. Its accurate demonstration is important for treatment, as it must be adequately excised to achieve optimal therapeutic benefit. Recent studies have demonstrated the difficulty in determining the presence of DCIS with dynamic low resolution MRI. 9,34 This may be attributed to the larger voxels needed to achieve a higher acquisition speed, which results in greater volume averaging effects. This problem can be corrected with higher spatial resolution and higher contrast. RODEO has been shown to reliably detect DCIS and characterize microcalcifications.57 We are now employing RODEO to localize margins of DCIS prior to excision. RODEO can accurately demonstrate the extent of DCIS.

What special considerations are needed for localization methods when minimally invasive therapy is used?

One of the major issues for breast MRI localization procedures is the “vanishing lesion” problem. The optimal contrast between tumor and parenchyma occurs at about two minutes after a bolus of gadolinium contrast. After about five minutes, the lesion begins to vanish into the background and is no longer visible. This effect virtually eliminates any form of real-time localization since the lesion will disappear so quickly.

A variety of stereotaxic methods have been employed successfully for biopsy and localization. However, some special problems will be encountered for when minimally invasive therapy is used.

Most MRI localization methods are extensions of a mammographic technique. Typically, a mammographic localization attempts to place a single wire through the center of a lesion prior to excision. Precision is not a major problem as long as the wire is reasonably close. The location of the wire relative to the lesion can be demonstrated on a mammogram obtained after the localization procedure.

MRI-directed treatment applications will require considerably more precision. The vanishing lesion problem means that repeat imaging after the procedure will not be possible. Accurate needle placement within and around the lesion is required to define the treatment field to include the lesion and an appropriate margin.

Real-time needle placement in open MRI systems has been effectively used for a variety of interventional purposes.10 This procedure may be useful for some breast lesions such a fibroadenomas that are well visualized on non-contrast images. For most small breast cancers, however, real-time localization in an open MRI is not likely to be effective since confirming images cannot be employed to validate appropriate needle placement. The vanishing lesion effect has the greatest impact on this approach. Another problem with the open MRI systems is lower overall imaging performance that makes definition of small lesions and their margins more difficult. Perhaps if longer acting contrast agents become available, real-time positioning would be become advantageous.

Frameless stereotaxic systems are widely used for head and neck applications.11 These systems use image data gathered with fiducial marks that are registered with a computer display to allow an interactive display with previously acquired images during the interventional procedure. Typically a high resolution image set is acquired and loaded into the machine. The patient is taken to the operating room, where the images guide the procedure without rescanning. This method works best when rigid, immovable structures such as bones are imaged. Because of the lack of structure in the breast, deformation of the breast during the procedure is a significant problem, which is addressed by some form of compression. One group has successfully used thermal setting plastic similar to the molds used in radiation therapy to form cast around the breast in order to maintain a fixed position during the procedure.11

The most common approach to stereotaxic breast MRI localization employs breast compression and a needle guide. A common needle guide uses a plate with multiple holes that are drilled at appropriate intervals within the plate. The best hole is selected on the MRI image and the needle is inserted through the hole a measured distance to the lesion. Another popular approach employs a needle holder to guide the needle though a window in the plate. Coordinates for the needle holder are obtained from the MRI image. Both of these approaches define a unique pathway to the lesion and are most typically used for single needle localizations or biopsy.13,14,29,31,45,53 These systems are not designed to approach multiple targets from the same entry or the same target from multiple entries.

Our group recently developed another approach to MRI guided needle placement that combines some of the attributes of freehand approaches with stereotaxic systems. Compression plates are drilled throughout with 1 cm holes so that access to the entire breast is possible. In addition, the protrusion of the breast through the holes grabs the skin and provides additional stability to prevent the breast from rolling when pressure is applied. Guidance is provided indirectly with a laser beam that is located at some distance from the field. The best access hole is selected on the MRI image. The distance from the hole to the lesion and two angles are obtained from the MRI. The angles are dialed into the laser positioner and the beam is centered on the selected hole. The tip of the needle is placed on the laser spot on the skin and the hub is aligned with the beam. As the needle is guided by hand, tactile sense is preserved and the trajectory can be tested intermittently by releasing the hub. If the hub bounces off the beam, the needle is bending off the trajectory.

We have found the deflection of MRI needles to be a particular problem. This system allows an easy correction for needle deflection. Multiple needles with different targets can be placed through the same entry or different entry sites can be selected with the needles converging on the same target. The latter approach can be used to simultaneously laser treat a lesion with multiple needles while thermally isolating the entry sites.7

What kinds of minimally invasive treatment methods are applicable to the breast?

Minimally invasive treatment methods typically employ some form of thermal injury that can be delivered with imaging guidance. There are some unique circumstances that must be considered for breast lesion therapy. Many of these therapies have been applied to the treatment of lesions such as metastatic colorectal cancer to the liver, where margin definition of the lesion is straightforward. As mentioned previously, breast cancer margins are difficult to determine and present perhaps the greatest challenge for imaging. In addition, inadequate treatment of the margin will adversely affect prognosis. Therefore, coordination of treatment delivery and margin definition is required for an effective minimally invasive breast-cancer treatment.

Cryotherapy uses a system that delivers the freezing effect of liquid nitrogen to a small area. Cryotherapy is now a popular method for the palliative treatment of liver lesions, particularly colorectal metastases.36 The size of the probe for cryotherapy is large and is usually applied with a surgical exposure. Freezing is not as effective at tumor ablation as hyperthermia. Some tumor cells may survive freezing. The treatment zone of cryotherapy is readily demonstrated on ultrasound, a significant advantage for this approach. Although generally widely available, the application of cryotherapy for breast cancer treatment has not been a popular option in research centers performing minimally invasive therapy. The technology is widely available, however, and the regulatory requirements are less stringent than with lasers.

Interstitial hyperthermia is a well-established method for ablating tissue. First introduced in the late 1980s, a variety of FDA approved devices are available for the treatment of solid tumors. Interstitial hyperthermia has been used for the treatment of liver tumors, head and neck tumors, brain tumors, prostatic enlargement, gynecologic tumors, and pancreatic carcinoma.1,6,32,39,40,43,50,60,61 Interstitial hyperthermia was initially applied exclusively with a laser. Other techniques have emerged including radiofrequency probes, focused ultrasound, and heated saline. A typical interstitial hyperthermia treatment would consist of heating for about 10 minutes at a temperature of about 60(C).

A variety of lasers have been used for interstitial hyperthermia. Recently, diode lasers have largely replaced NdYAG lasers because of their small size, portability, use of standard 110 v current, and lower cost.32 Originally, bare tip fibers were used. There is debate over the issue of pre-charring the laser tip. Proponents of pre-charring claim better thermal conduction as a result. Others claim that light penetrates better if charring does not occur. About a 1 cm treatment zone can be expected to result from a pre-charred laser tip when tissue is exposed to 2-3 W of continuous laser power for about 10 minutes. Recent developments use diffuser tips, extending the treatment zone to up to 3 cm. Precise temperature control at the laser tip can be employed to reduce the time of treatment to about 3 minutes. An advantage of lasers is their small size. A bare fiber can be inserted through a needle as small as 22 g. The laser energy may be split into up to four fibers for simultaneous treatment through multiple needles. Diffuser tip fibers require larger needles of around 14 g. Laser fibers themselves do not cause MRI artifacts. The compatibility of lasers with MRI may be helpful as phase sensitive temperature maps are used for interactive therapy.16

Interstitial hyperthermia may also be delivered with radiofrequency. FDA approved radiofrequency therapy devices have been developed for the treatment of colorectal metastases for the liver. These devices consist of wires that are extended into the tissue which conduct radiofrequency energy to heat the tissue in a localized region. Radiofrequency treatment zones are typically up to 3 cm in diameter, significantly larger than a bare tip laser fiber. Radiofreqency treatment devices are less expensive than lasers and the regulatory requirements are not as strict. The disadvantage of radiofrequency treatment devices is the larger probe size and the use of metal that produces MRI artifacts.58 Although MRI compatible devices are made, they are not likely to be compatible with phase sensitive MRI temperature mapping sequences. The limited use of radiofrequency probes for breast cancer treatment has been limited to ultrasound guidance.5

Focused ultrasound has great promise as a minimally invasive treatment device since it may be applied non-invasively on the skin surface.41 A series of transducers focus the ultrasound energy on a point in the tissue. This point is rapidly heated to the point of destruction. Although focused ultrasound is rapid, it does not encompass a large amount of tissue. In the future, imaging guidance will map a course for the ultrasound ablation, which will consist of a series of point ablations that eventually will encompass the entire tumor boundary. Focused ultrasound is MRI compatible. Machines are being designed for use inside the bore of the MRI. Focused ultrasound has a disadvantage in that tissue may move during the course of the therapy, changing the initial treatment map. Since a needle is not needed in the tissue, access to the tissue for pathologic confirmation will not be available. Since pathologic markers are needed for breast cancer, access to the tumor with a needle is a part of management. If we continue to require these markers for therapeutic guidance, the non-invasive advantage of focused ultrasound treatment may not be practically realized.

How much minimally invasive breast therapy has been performed to date?

With the societal importance of breast cosmesis and the availability of current methods, one may ask why more clinical trials are not open for the validation of minimally invasive therapy of the breast. Most new therapies are employed first on individuals where there are few alternatives. For example, tamoxifen was first demonstrated to be effective in women who failed conventional therapy. Now tamoxifen is used a first line chemotherapy. Unfortunately, this approach is not applicable to minimally invasive therapy. The benefits of minimally invasive therapy can only be achieved in the treatment of small breast cancers. These cancers are now being treated with an outstanding prognosis. The ethical dilemma is can we subject these individuals to a new therapy with unknown effectiveness when we know the standard treatment has a great potential for curing the disease? This concern has greatly limited progress on the clinical implementation of new minimally invasive treatment methods.

Some researchers have addressed this dilemma by testing the methodology on patients with benign fibroadenomas.41,18 These lesions have negligible malignant potential, but many women prefer to have them removed. Fibroadenomas usually present as palpable masses and can produce pain. Since there is little downside risk, these women can be treated with the new therapy alone and followed clinically.

Minimally invasive therapy has been used successfully in a small group of these patients, with excellent results. These findings illustrate the potential for minimally invasive therapy to improve cosmesis associated with lumpectomy surgery. Most patients experience relief of pain and the mass associated with fibroadenomas after minimally invasive therapy. There is little or no deformity after the treatment. The treatment of fibroadenomas, however, is not likely to be a major application of this new therapy. Since fibroadenomas have little malignant potential and often involute when left alone, the best treatment option is probably no treatment at all.

Most clinical trials using minimally invasive treatment of breast cancer have been undertaken in women who subsequently undergo surgery (22-27). In this situation, the tumor or a portion of the tumor is treated with the new therapy. After surgical removal, the treated tumor is examined pathologically for evidence of cell death. The ability of pathology to accurately determine cell death has been debated. If the surgery is performed shortly after interstitial hyperthermia, routine H & E staining may not show evidence of cell death. Our group prefers to use the proliferating cell nuclear antigen stain (PCNA), which stains nuclei that have abundant turnover of DNA. In areas of thermal ablation, there is little PCNA activity, indicating likely cell death. The PCNA stain works well when the treatment zone lies within the tumor where the nuclear staining is apparent. The demonstration of treatment zones in normal tissue, however, is problematic. If a delay of a few days is achieved between the minimally invasive therapy and surgery, demonstration of treatment zones is straightforward. Unfortunately, this delay is impractical in most American settings. In the United Kingdom, however, such delays are typical and have facilitated excellent demonstration of effective treatment.

Ultimately, a clinical trial will be initiated to test minimally invasive breast cancer treatment. A pilot study that explores the feasibility of this new therapy in terms of side effects will be the first step. To determine equivalence of this therapy to surgical lumpectomy will require a prospective, randomized multicenter trial. Since the expected five-year recurrence rate will be only a few percent, large patient numbers will be needed to determine statistical significance. We have a number of developments that will need to be standardized before a trial this ambitious can be initiated. A collaborative effort among industry, academia, and government will be the most expedient method for launching this effort.

Summary

The success of breast MRI in determining negative predictive value for breast cancer has made the minimally invasive therapy of breast cancer a clinical possibility. The challenge for MRI technology is the development of reliable methods for excluding DCIS as well as invasive carcinoma. Stereotaxic devices are becoming available for accurate localization of breast cancers. Greater flexibility and precision is needed for minimally invasive therapy applications. Treatment devices are rapidly being developed for other organs that may benefit breast cancer treatment. Coordinating the delivery of therapy with the MRI is likely to be a successful approach.

Perhaps the greatest challenge is the development of a clinical trial that assures patient safety and provides data that would validate this new treatment as an alternative to traditional surgery. More work will be needed to provide the tools for this effort. It is clear that society wants a minimally invasive option as an alternative to the disfigurement of surgery. The benefits of this new therapeutic approach are strong incentives that will drive the technological development in upcoming years.

References

1. Amin Z, Donald JJ, Masters A, et al. Hepatic metastases: Interstitial laser photocoagulation with real-time US monitoring and dynamic CT evaluation of treatment. Radiology 187:339-347, 1983.
2. Bader J, Lippman ME, Swain SM. Preliminary report of the NCI early breast cancer (BC) study: A prospective randomized comparison of lumpectomy (L) and radiation (XRT) to mastectomy (M) for Stage I and II BC (abstract). Int J Radiat Oncol Biol Phys 13 (suppl 1):160, 1987.
3. Blichert-Toft M. A Danish randomized trial comparing breast conservation with mastectomy in mammary carcinoma. Br J Cancer 62 (suppl 12):15, 1990.
4. Blichert-Toft M, Brincker H, Andersen JA, et al. A Danish randomized trial comparing breast-preserving therapy with mastectomy in mammary carcinoma: Preliminary results. Acta Oncologica 27:671-677, 1988.
5. Bohm T, Hilger I, Muller W. Saline-enhanced radiofrequency ablation of breast tissue: An in vitro feasibility study. Invest Radiol 35:149- 157, 2000.
6. Bown SG. Phototherapy of tumours. World J Surg 7:700-709, 1983.
7. Cardwell DM, Harms SE, Lindquist D, et al. Laser directed portable MRI stereotactic system. Radiology 217P:268, 2000.
8. Cross MJ, Harms SE, Cheek JH, et al. New horizons in the diagnosis and treatment of breast cancer using magnetic resonance imaging. Am J Surg 166:749-755, 1993.
9. Daniel BL, Yen Y-F, Glover GH, et al. Breast disease: dynamic spiral MR imaging. Radiology 209(2):499-509, 1998.
10. Daniel BL, Birdwell RL, Ikeda DM, et al. Breast lesion localization: freehand, interactive MR image-guided technique. Radiology 207(2):455-463, 1998.
11. deSouza NM, Gilderdale DJ, Coutts GA, et al. Magnetic resonance imaging guided breast biopsy using a frameless stereotactic technique. Clin Radiol 51:425, 1996.
12. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. New Engl J Med 320:822-828, 1989.
13. Fischer U, Vosshenrich R, Bruhn H, et al. Breast biopsy guided with MR imaging: experience with two stereotaxic systems. Radiology 193(P):267, 1994.
14. Fischer U, Vosshenrich R, Keating D, et al. MR-guided biopsy of suspect breast lesions with a simple stereotaxic add-on-device for surface coils. Radiology 192(1): 272-273, 1994.
15. Ghossein NA, Alpert S, Barba J, et al. Importance of adequate surgical excision prior to radiotherapy in the local control of breast cancer in patients treated conservatively. Arch Surg 127:411-415, 1992.
16. Graham SJ, Bronskill MJ, Henkelman RM. Time and temperature dependence of MR parameters during thermal coagulation of ex vivo rabbit muscle. Magn Res Med 39:198-203, 1998.
17. Haga S; Makita M; Shimizu T et al. Histopathological study of local residual carcinoma after simulated lumpectomy. Surg Today 25:329-33, 1995.
18. Hall-Craggs MA. Interventional MRI of the breast: Minimally invasive therapy. Eur Radiol 10:59, 2000.
19. Harms SE, Mumtaz H, Klimberg SV, et al. Magnetic resonance imaging-directed laser lumpectomy. Breast Diseases: A Year Book Quarterly 9(4):336-338, 1999.
20. Harms SE, Mumtaz H, Hyslop B, et al. RODEO MRI guided laser ablation of breast cancer. Society of Photo-Optical Instrumentation Engineers Proceedings 3590:484-489, 1999.
21. Harms SE, Flamig DP, Hesley KL, et al. Magnetic resonance imaging of the breast. Magn Reson Q 8(3):139-155, 1992.
22. Harms SE, Flamig DP, Hesley KL, et al. Fat suppressed three-dimensional MR imaging of the breast. RadioGraphics 13:247-267, 1993.
23. Harms SE, Flamig DP, Hesley KL, et al. Breast MRI: rotating delivery of excitation off-resonance: Clinical experience with pathologic correlations. Radiology 187:493-501, 1993.
24. Harms SE, Flamig DP. MR imaging of the breast: Technical approach and clinical experience. RadioGraphics 13:905-912, 1993.
25. Harries SA, Masters A, Lees WR, et al. Eur J Surg Oncol 19:217, 1993.
26. Harries SA, Amin Z, Smith MEF, et al. Interstitial laser photocoagulation as a treatment for breast cancer. Br J Surg 81:1617-1619, 1994.
27. Hatschek T, Fagerberg G, Stal O, et al. Cytometric characterization and clinical course of breast cancer diagnosed in a population-based screening program. Cancer 64:1074-1081, 1989.
28. Heywang-Kobrunner SH, Schlegel A, Beck R, et al. Contrast-enhanced MRI of the breast after limited surgery and radiation therapy. J Comput Assist Tomogr 17(6):891-900, 1993.
29. Heywang-Koebrunner SH, Halle MD, Requardt H, et al. Optimal procedure and coil design for MR imaging-guided transcutaneous needle localization and biopsy. Radiology 193(P):267, 1994.
30. Holland R, Veling SHJ, Mravunac M, et al. Histologic multifocality of Tis, T1-2 breast carcinomas: Implication for clinical trials of breast-conserving surgery. Cancer 56:979-90, 1985.
31. Hussman K, Renslo R, Phillips JJ, et al. MR mammographic localization. Radiology 189(3):915-917, 1993.
32. Jacques SL, Rastegar S, Motamedi M, et al. Liver photocoagulation with diode laser (805 nm) vs Nd:YAG laser (1064 nm). Proc SPIE 1646:107-117, 1992.
33. Joensuu H, Taikkanen S. Cured of breast cancer. J Clin Oncol 13:62-69, 1995.
34. Kuhl CK, Mielcareck P, Klaschik S, et al. Dynamic breast MR imaging: Are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology 211:101-110, 1999.
35. Lagios MD, Westdahy PR, Rose MR. The concept and implications of multicentricity in breast carcinoma. In Sommers SG, Rosen PP (eds): Pathology Annual. New York: Appleton-Centur y-Crofts, 1981, pp 83-102.
36. Lee FT Jr, Mahvi DM, Chosy SG, et al. Hepatic cryosurgery with intraoperative US guidance. Radiology 202:624-632, 1997.
37. Leitner SP, Swern AS, Weinberger D, et al. Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a,bN0M0). Cancer 76:2266-2274, 1995.
38. Letton AH, Mason EM, Ramshaw BJ. Twenty-year review of a breast cancer screening project: Ninety-five percent survival of patients with nonpalpable cancers. Cancer 77:104-106, 1996.
39. Masters A, Bown SG. Interstitial laser hyperthermia in tumour therapy. Ann Chir Gynaecol 79:244-251, 1990.
40. Matthewson D, Coleridge-Smith P, O’Sullivan JP, et al. Biological effects of intrahepatic neodymium:yttrium-aluminum-garnet laser photocoagulation in rats. Gastroenterology ; 93:550-557, 1987.
41. McDannold N, Hynynen K, Wolf D, et al. MRI evaluation of thermal ablation of tumors with focused ultrasound. JMRI 8:91-100, 1998.
42. Mumtaz H, Hall-Craggs MA, Wotherspoon A. Laser therapy for breast cancer: MR imaging and histopathologic correlation. Radiology 200(3):651-658, 1996.
43. Nolsoe CP, Torp-Pedersen S, Burcharth F, et al. Interstitial hyperthermia of colorectal liver metastases with a US-guided Nd-YAG laser with a diffuser tip: A pilot clinical study. Radiology 187:333-337, 1993.
44. Orel SG, Schnall MD, LiVolsi VA, et al. Suspicious breast lesions: MR imaging with radiologic-pathologic correlation. Radiology 190:485-493, 1994.
45. Orel SG, Schnall MD, Newman RW, et al. MR imaging-guided localization and biopsy of breast lesions: initial experience. Radiology 193:97-102, 1994.
46. Pezner RD, Lipsett JA, Desai K, et al. To boost or not to boost: decreasing radiation therapy in conservative breast cancer treatment when “inked” tumor resection margins are pathologically free of cancer. Int J Radiat Oncol, Biol, Phys 14:873-877, 1988.
47. Robinson DS, Parel JM, Denham DB, et al. Interstitial laser hyperthermia model development for minimally invasive therapy of breast carcinoma. J Am Coll Surg 186:284-292, 1998.
48. Rosen PP, Groshen S, Saigo PE, et al. A long-term follow-up study of survival in stage 1 (T1N0M0) and stage II (T1 N1M0) breast carcinoma. J Clin Oncol 7:355-366, 1989.
49. Ryoo MC, Kagan AR, Wollin M, et al. Prognostic factors for recurrence in the conservative management of early breast cancer: A 25 year follow-up. Int J Radit Oncol Biol Phys 17:719-725, 1989.
50. Sarrazin D, Le MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 14:177-184, 1989.
51. Schatz SW, Bown SG, Wyman DR, et al. Low power interstitial Nd-YAG laser photocoagulation in normal rabbit brain. Lasers Med Sci 7:433-439, 1992.
52. Schmidt-Ullrich R, Wazer DE, Tercilla O, et al. Tumor margin assessment as a guide to optimal conservation surgery and irradiation in early stage breast carcinoma. Int J Radiat Oncol Biol Phys 17:733-738, 1989.
53. Schnall MD, Orel SG, Connick TJ. MR guided biopsy of the breast. MRI Clin No Am 4:585-590, 1984.
54. Schnitt SJ, Abner A, Gelman R, et al. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer 74:1746-1751, 1994.
55. Schwartz GF, Patchesfsky AS, Feig SA, et al. Multicentricity of nonpalpable breast cancer. Cancer 45:2913-2916, 1980.
56. Seidman H, Gelb SK, Silvergerg E, et al. Survival experience in the breast cancer detection demonstration project end results. CA Cancer J Clin 5: 258-290, 1987.
57. Soderstrom CE, Harms SE, Copit DS, et al. 3D RODEO breast MRI of lesions containing ductal carcinoma in situ. Radiology 201:427- 432, 1996.
58. Solbiati L, Goldberg SN, Ierace T, et al. Hepatic metastases: Percutaneous radio-frequency ablation with cooled-tip electrodes. Radiology 205:367-373, 1997.
59. Spivak B, Khanna MM, Tafra L, et al. Margin status and local recurrence after breast-conserving surgery. Arch Surg 129:952-957, 1994.
60. Steger AC, Lees WR, Walmsley K, et al. Interstitial laser hyperthermia: A new approach to local destruction of tumors. Br Med J 299:362-365, 1989.
61. Storm FK, Sliberman AW, Ramming KR, et al. Clinical thermochemotherapy: A controlled trial in advanced cancer patients. Cancer 53:863-868, 1984.
62. Veronesi U, Banfi A, Del Vecchio M, et al. Comparison of Halsted mastectomy with quadrantectomy, axillary dissection, and radiotherapy in early breast cancer: Long-term results. Eur J Cancer Clin Oncol 22:1085-1089, 1986.

Cryosurgery: Does it Have a Role in the Breast? Susan M. Love, M.D. MBA, Adjunct Professor of Surgery UCLA, Pacific Palisades, CA

Surgical excision has been the gold standard for dealing with benign and malignant breast lesions for decades. The argument for surgical removal of a lesion rested on the need to determine pathological information as well as to measure markers. Removing the lesion has the added benefit of local control. The increasing use of large core needle biopsies under ultrasound or stereotactic guidance has opened the way to a reevaluation of the need to remove breast lesions. Pathology and markers can easily be measured in large core biopsies. This leaves us with the question as to whether there are other ways to ablate tumors and achieve local control.

Since the effectiveness of cryosurgery for ablation of for skin, hepatic, ocular lesions and prostate cancers had been demonstrated, it is reasonable to evaluate its use in the breast. We established a model in C3H mice of 1 cm subcutaneous breast cancers. After anesthetizing the mice we employed a 1 mm cryolite probe (Cryomedical Sciences, Rockville MD) to freeze the tumor while monitoring the temperature in the center of the tumor, margin of the tumor and centrally in the mouse. First we evaluated varying freeze thaw cycles, tumor temperatures, margin temperatures and time to thaw. Animals who had their tumors frozen to -40o for three freeze thaw cycles demonstrated a loss of tumor mass and residual wet or dry necrosis with disappearance of the tumor mass between 12-20 days. In this initial phase thirteen animals had complete disappearance of tumor and four animals had recurrence of tumor. In this pilot study local ablation of breast tumors with cryosurgery was a feasible alternative to surgery in mice.

Cryosurgery is particularly well suited for use in the breast for a number of reasons. First of all, the ice ball that is created is extremely well visualized on ultrasound due to its highly echo-reflective properties. This allows for very accurate monitoring of ice ball growth, a high degree of procedural control, and a tailoring of the therapy directly to the pathology. Sterile normal saline or local anesthetic can be repeatedly injected between the skin and forming ice ball and serves as a protective barrier. The ultra-cold temperatures created by modern cryoablation systems are anesthetic in nature, thus allowing adequate treatment using local anesthesia without sedation.

In a study sponsored by Sanarus a 2.4-mm cryoprobe was used under two different protocols to evaluate its effectiveness in both benign and malignant disease. Fifty-seven biopsy-proven fibroadenomas were treated in 46 patients. Early in the study, 10 patients were treated in an ambulatory surgery setting with moderate intravenous sedation and local anesthesia. The remaining patients were treated in an office setting. The first 18 of these patients treated in the office received local anesthesia with 100 mcg of I.V. Fentanyl. All subsequent office-based treatments were delivered using local anesthesia only. The first 22 fibroadenomas in 19 patients were treated with a 10-minute freeze followed by a 10-minute thaw and another 10-minute freeze. No cryo-related findings (e.g. calcifications or scarring) were noted on these patient’s mammograms at 6- or 12-months post treatment. The subsequent fibroadenomas were treated with an algorithm based on tumor size that entailed decreased treatment times and reduced gas flow in order to more closely tailor the therapy to the tumor. This algorithm provides a total treatment time (double freeze and thaw) of 18 minutes for a 2-cm fibroadenoma. Mean pre-treatment maximum tumor diameter by ultrasound for all tumors was 1.9 + 0.8 cm. In 25 tumors that have reached 12-month follow up, average tumor volume reduction was 90%. No significant complications were noted. One mastitis and two hematomas responded to oral antibiotics and time, respectively. Cosmetic results have been outstanding.

A pilot study is ongoing to evaluate the use of cryoablation in core biopsy proven breast cancers that are to be resected one to three weeks later. Of the first eleven patients treated in this series, four were treated in ambulatory surgery under local anesthesia with intravenous sedation. The others received only local anesthesia in the office. Tumors had a mean maximum diameter of 13-mm. One case had a double 8-minute freeze with an intervening 8-minute thaw. The others were double ten-minute freezes. All but one patient had their tumors completely destroyed by the cryoablation procedure. This patient had an area of DCIS at the margin.

Cryoablation is an excellent modality for the treatment of breast fibroadenomas today. It use in malignant tumors could include cryolumpectomy as well as cryoablation to achieve local control. Can interstitial ablation be used to destroy breast tumors locally through tiny skin incisions? The answer is clearly yes. Radiofrequency, laser, high frequency ultrasound, and cryoablation have all been demonstrated to successfully do so. What remains to be elucidated is the appropriate clinical application of these technologies. And the questions will be not only are these ablative techniques as good as surgery but could they be better? Could there be immunological benefits to any of these techniques? Could the ablation of a tumor either immediately prior to or in place of its surgical excision have an impact on the spill of tumor cells in the blood compared to lumpectomy? Would such an impact have clinical relevance? Of obvious concern is the issue of margin evaluation in cases where a breast cancer is not going to be removed. But improvements in imaging and adjuvant therapies that may render this question less important. Less obvious in the definition of “minimally invasive” are such items as the ability of an interstitial ablation technique to demonstrate superior cosmetic results or to be performed using strictly local anesthesia in an office environment that will be more comfortable for the patient.

Brachytherapy to the Tumor Bed Alone Versus Whole Breast Irradiation Frank A. Vicini, M.D., Clinical Assoc. Professor, Director Radiation Oncology, William Beaumont Hospital, Royal Oak, MI

Introduction: The combination of lumpectomy followed by radiation therapy (RT), referred to as breast conserving therapy (BCT) is now widely accepted as an equivalent treatment option for most women with clinical stage I/II invasive breast cancer. One question that has remained unanswered, however is whether or not the entire breast needs to be treated, or only a more limited volume of tissue surrounding the tumor bed. Traditionally, patients treated with BCT have been irradiated to the entire breast. However, most of the potential long-term complications and time constraints of BCT result from either whole-breast or nodal irradiation. In addition, giving radiotherapy to the entire breast essentially precludes giving further RT in the event that a patient develops a new primary tumor.

In recognition these problems, the option of partial-breast irradiation (PBI) has been explored. This concept lends itself to much shorter treatment schemes than whole breast irradiation, as the toxicities to the breast and surrounding tissues should be lessened by treating only a portion of the breast. In addition, if a significantly shortened treatment scheme could be shown to produce equivalent outcome to traditional six weeks of whole breast irradiation, it would substantially improve the quality of life of patients and allow easier integration of radiotherapy with chemotherapy. Just as important, a logistically simpler and quicker treatment could potentially increase the breast conservation option to more women and reduce the costs of post-lumpectomy radiation. To this end, several groups began to explore accelerated treatment schemes in the 80’s and 90’s. Both external beam radiation therapy (EBRT) and brachytherapy were employed(1-14). The success of these early phase I/I and III studies has been inconsistent and will be reviewed as well as the outcome of PBI using brachytherapy alone at William Beaumont Hospital.

Materials and Methods: From 1/93 through 1/02, 197 cases of early stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant (120 cases using a low dose rate implant (50 Gy over 96 hours) and 77 cases using a high dose rate implant (32 Gy in 8 fractions over 4 days or 34 Gy in 10 fractions over 5 days). Locoregional control, distant metastases (DM), disease free survival (DFS), overall survival (OS), and cause-specific survival (CSS) were calculated.

In order to estimate the effects of selection bias and short follow-up on treatment results, each brachytherapy patient was matched with one EBRT patient derived from a reference group of 1388 patients treated with standard BCT at the same institution. Patients were matched for age, tumor size, histology, margins of excision, absence of extensive intraductal component (EIC), nodal positivity, estrogen receptor status, the use of adjuvant tamoxifen, and the use of adjuvant chemotherapy. Follow-up for EBRT patients was truncated at the same time interval as each matched brachytherapy patient. Median follow-up for the EBRT and brachytherapy groups was 50 months and 50 months, respectively.

Results: Three local and one regional failures were detected in patients treated with brachytherapy alone (5-yr actuarial rates of 1.9% and 1.3%, respectively. Three patients failed distantly. No adverse sequelae were noted and cosmetic results were good/excellent in > 90% of patients. No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral failure, locoregional failure or DM between EBRT or brachytherapy patients.

Conclusions: Accelerated treatment of breast cancer using an interstitial implant to deliver RT to the tumor bed alone in 4-5 days appears to produce equivalent 5-year results compared to conventional EBRT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach and the potential advantages/disadvantages of accelerated treatment.

Reference List

1. Kuske, R. R., Bolton, J. S., and Hanson, W. RTOG 95-17: A phase I/II trial to evaluate brachytherapy as the sole method of radiation therapy for stage I and II breast carcinoma. 1-34. 1998.
2. King TA, Bolton JS, Kuske RR, Fuhrman GM, Scroggins TG, Jiang XZ. Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am.J Surg 2000;180:299-304.
3. Perera F, Engel J, Holliday R, Scott L, Girotti M, Girvan D et al. Local resection and brachytherapy confined to the lumpectomy site for early breast cancer: a pilot study. J Surg Oncol 1997;65:263-7.
4. Polgar, C., Fodor, J., Orosz, Z., Major, T., Takacsi-Nagy, Z., Mangel, L. C., Somogyi, A., Sulyok, Z., Toth, J., and Nemeth, G. Sole high-dose- rate brachytherapy of the tumor bed after conservative surgery for T1 breast cancer: 4 year results of a phase I-II study and initial findings of a randomized phase III trial. 2001.
5. Vicini FA, Baglan KL, Kestin LL, Mitchell C, Chen PY, Frazier RC et al. Accelerated treatment of breast cancer. J Clin.Oncol 2001;19:1993- 2001.
6. Fentiman IS, Poole C, Tong D, Winter PJ, Mayles HM, Turner P et al. Iridium implant treatment without external radiotherapy for operable breast cancer: a pilot study. Eur.J Cancer 1991;27:447-50.
7. Fentiman IS, Poole C, Tong D, Winter PJ, Gregory WM, Mayles HM et al. Inadequacy of iridium implant as sole radiation treatment for operable breast cancer. Eur.J Cancer 1996;32A:608-11.
8. Cionini, L. Pacini P. Marzano S. et al. Exclusive brachytherapy after conservative surgery in cancer of the breast. Lyon Chir 89, 128. 1993.
9. Clarke DHVFAJHea. High dose rate brachytherapy for breast cancer. In: Nag S. High dose rate brachytherapy: A textbook, First ed. Armonk, N.Y.: Futura Publishing, 1994:321-9.
10. Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospital breast conservation trial: an update at 8 years from inception. Clin.Oncol (R.Coll.Radiol) 1993;5:278-83.
11. Ribeiro GG, Dunn G, Swindell R, Harris M, Banerjee SS. Conservation of the breast using two different radiotherapy techniques: interim report of a clinical trial. Clin.Oncol (R.Coll.Radiol) 1990;2:27-34.
12. Magee B, Swindell R, Harris M, Banerjee SS. Prognostic factors for breast recurrence after conservative breast surgery and radiotherapy: results from a randomised trial. Radiother.Oncol 1996;39:223-7.
13. Wazer DE, Lowther D, Boyle T, Ulin K, Neuschatz A, Ruthazer R et al. Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer. Int J Radiat Oncol Biol Phys 2001;50:107-11.
14. Krishnan L, Jewell WR, Tawfik OW, Krishnan EC. Breast conservation therapy with tumor bed irradiation alone in a selected group of patients with stage i breast cancer. Breast J 2001;7:91-6.

Intraoperative Full-Dose Radiotherapy in Limited-Stage Breast Cancer Conservatively Treated Umberto Veronesi, M.D., Scientific Director, European Institute of Oncology, Milan, Italy

The development of Intraoperative Radiotherapy was based on the evidence that local recurrences after breast conserving surgery occur mostly in the quadrant harbouring primary carcinoma. The main objective of postoperative radiotherapy appears therefore to be the sterilization of residual cancer cells in the operative area while irradiation of the whole breast may be avoided. We have developed a new technique of intraoperative radiotherapy of a breast quadrant after the removal of the primary carcinoma. A mobile linear accelerator with a robotic arm is utilized delivering electron beams able to produce energies from 3 to 9 MeV. Through a perspex applicator the radiation is delivered directly to the mammary gland and to spare the skin from the radiation the skin margins are stretched out of the radiation field. To protect the thoracic wall an aluminium-lead disc is placed between the gland and the pectoralis muscle.

Different dose-levels were tested from 10 to 21 Gy without important side effects. We estimated that a single fraction of 21 Gy is equivalent to 60 Gy delivered in 30 fractions at 2 Gy/fraction.

Seventeen patients received a dose of IORT of 10 to 15 Gy as an anticipated boost to external radiotherapy, while 86 patients received a dose of 17-19-21 Gy intraoperatively as a complete treatment. The follow-up time of the 101 patients varies from 15 to 30 months (mean follow-up time 20 months).

The IORT treatment was very well accepted by all patients, either due to the rapidity of the radiation course in case of IORT as a whole treatment or to the shortening of the subsequent external radiotherapy in case of IORT as an anticipated boost. We believe that single dose intraoperative radiotherapy after breast resection for small mammary carcinomas may be an excellent alternative to the traditional postoperative radiotherapy.

Accelerated Treatment with Increased Fractionation for Breast Irradiation Tim Whelan, B.M., B.Ch., M.Sc., Associate Professor, Dept. of Medicine and Director, Supportive Cancer Care Research Unit, McMaster University, Ontario, Canada

A number of randomization trials have demonstrated that breast irradiation following lumpectomy reduces the risk of recurrence of cancer in the breast and prevents the need for mastectomy. Breast irradiation is usually given daily for five to six weeks. However, the optimal fractionation for breast irradiation is unclear. Retrospective studies have suggested that more rapid fractionation schedules for breast irradiation may be as effective. A randomized controlled trial was performed in Canada to determine whether a three week course of radiation (42.5 Gy in 16 fractions administered over 22 days) was as effective a five course (50 Gy in 25 fractions administered over 35 days) in women with node negative breast cancer with clear resection margins following lumpectomy. The primary outcome was local recurrence in the treated breast. An important secondary outcome was breast cosmesis as measure of late morbidity for radiation therapy. Between April of 1993 and September of 1996, 1,234 women were randomized. Median follow-up is now more than five years. Rates of local recurrence free survival were similar in both treatment arms. Cosmetic outcome assessed at three and five years post randomization was also similar between the two treatment groups. The results of this trial are consistent with earlier studies of hypofractionation and support that the shorter three-week schedule of radiation is as an acceptable alternative to the longer five-week schedule. Such a schedule is attractive because it is more convenient for patients and less resource intensive.

How to get around involved margins an anatomical challenge Werner P. Audretsch, M.D., Chief Dept. of Breast Surgery Metropolitan Hospital, Dusseldorf, Germany

Classification
INVOLVED MARGINS are classified by microscopic examination as R1 or by intraoperative examination as R2 resection. Untreated involved margins are a marker and a precursor of a limited outcome.

Problem
In studies of our own, we have investigated the influence of biological and anatomical factors on local recurrence and the influence on prognosis in 2875 patients treated with total or partial mastectomy. Both histological-anatomical characteristics and tumour biological factors influence the local risk to an equal degree. It is striking that an early local recurrence leads to an extremely bad prognosis. This is especially the case following partial mastectomy. In the analysis of multiple variance, the factor margin is highly significant as an independent predictor (P=0.0002) for loco-regional early recurrence. This is followed by the biological factor (P=0.0039) progesterone receptor and by tumour size (P=0.0382).

Diagnosis
The assessment is based on a three-dimensional reconstruction of the extension of the lesion in the tumor specimen by the pathologist.

Type of involvement:

• Surrounding matrix
• Deep margins
• Overlaying skin
• Margin’s status together with local control are the significant determinants of surgical quality.

Etiology

• Young patients (<35 y, EORTC 22881)
• Non palpable lesion
• Non palpable diameter of the lesion extending the palpable mass
• Partial occult lesion larger than expected from standard imaging
• Gaps between foci
• Extended intraductal component
• Tumors in the border line of the breast close to the chest wall
• Lymph vessel invasion

Prognostic value
Results from a worldwide overview (Richard Peto, NIH Consensus, November 2000) suggest that a quarter of isolated local recurrences will result in death from breast cancer, deaths that would not otherwise have happened. Avoiding 20 local recurrences will lead to the avoidance of 5 breast cancer deaths in 15 years.

The EORTC-Study 22881 has made clear the significance of free margins for prognosis, especially in young patients below the age of 35 years.

Looked at from this point of view, the creation of free margins in connection with a cosmetic result is a decisive factor in BCT and in cases of mastectomy reconstruction.

Treatment
Cascade of decisions:

• Re-excision; but “first bite is the best” (Silverstein)
• Radiotherapy; but “bad surgery can not always be solved by good radiotherapy” (Batelink)
• Systemic chemotherapy; has a local effect (NSABP B6, NSABP-B18)
• Systemic hormontherapy; has a local effect (Neo-adjuvant anastrozole trial)
• Skin sparing mastectomy or total mastectomy following breast conserving surgery
• Combined radiotherapy and chemotherapy for partial mastectomy with R1 resection (in cases of >3 node positive primaries); results from our case control study: only 22% ypT+, residual tumor i.e. 78% ypT0, complete pathologic response after salvage mastectomy.
• Surveillance including mammogram, ultrasound, MRI
• Salvage mastectomy in case of uncertain local symptoms

The NSABP-B18-Study was able to prove the equal value of a preoperative and adjuvant chemotherapy.

Prevention

• Ultrasound needle framing of the mass
• MRI for breast conserving surgery in young patients
• Widening of excision without distorsion

Oncological and reconstructive operative procedures for the prevention and the solution of this conflict of aims can be summarised under the term oncoplastic surgery or coupled operations for partial and total mastectomies.

Skin Sparing Mastectomies Rache M. Simmons, MD FACS, Associate Professor of Surgery, Strang Weill-Cornell Breast Center, New York Presbyterian Hospital Weill Medical College of Cornell University, New York, NY

Skin Sparing Mastectomy and Immediate Breast Reconstruction

• Fortunately, most women diagnosed with breast cancer can be treated with breast conserving surgery.
• With those women who require or desire mastectomy, consideration should be given to optimize the cosmetic result with skin sparing mastectomy and immediate breast reconstruction

Advantages of Immediate Breast Reconstruction with Skin Sparing Mastectomy

• Improve body image and decrease psychological trauma of a breast cancer diagnosis
• Medically beneficial to avoid additional episode of anesthesia and recovery
• More cost effective
• Many patients will not pursue second operation for delayed reconstruction

Skin Sparing Mastectomy (SSM) Resection of nipple/areolar complex Resection of existing biopsy scar Removal of entire breast parenchyma +/- Axillary dissection Limited skin incision

SSM Incisions

Additional Incision Types with SSM • Periareolar with medial and lateral extensions 1 • Separate incision in the axilla to facilitate axillary dissection2,3

1 Slavin, et al, PRS, 102, 1998

2 Hildalgo, PRS, 102, 1998

3 Toth, PRS, 104, 1999

Aesthetic Advantages of SSM

• Smaller incisions
• Minimal skin resected in procedure
  – Skin envelope retained
• Improved symmetry with contralateral breast

Simmons, Ann Surg Onc, 6, 1999

Is Axillary Dissection Possible with SSM?

• Access through any of SSM incisions
• No decreased ability to remove axillary contents or perform sentinel node biopsy
• Average number of lymph nodes removed with SSM 18.0 and with NSSM 19.0
• Are There Increased Local Complications with SSM?
• Technically more challenging than NSSM
• More limited exposure through smaller incisions

Higher potential for flap injury or loss??

Native Skin Flap Epidermolysis/Skin Loss•

• most common with reduction type incision
  Carlson, Ann of Surg. 225, 1997

Breast Cancer Stage with SSM

Simmons, Ann Surg Onc, 6, 1999
Toth, PRS, 104, 1998
Slavin, PRS, 102, 1998
Carlson, Ann of Surg, 225, 1997

Local Recurrence Rate with SSM Simmons, SSO Abstract 2002 Carlson, Ann Surg, 225, 1997 Newman, Ann Surg Onc, 5, 1998 Distant Recurrence Rate with SSM SSM 2.9% (3/103) NSSM 1.5% (2/134) P=NS Simmons, SSO Abstract 2002

Methods of Immediate Reconstruction

Skin Sparing Mastectomy Conclusions Compared to NSSM:

• SSM with immediate reconstruction offers superior aesthetic results
• SSM has comparable local and distant recurrence rates
• No higher incidence of skin flap loss

SSM should be considered:

• DCIS, T1 and T2 carcinoma, T3 without skin involvement
• With or without sentinel node biopsy or axillary dissection
• In conjunction with all types of immediate reconstruction
• No contraindication to adjuvant chemotherapy or radiation therapy

SSM not indicated:

• Skin involvement or Inflammatory breast carcinoma

Areolar-Sparing Mastectomy

• Historically mastectomy has included resection of the nipple/areolar complex
• Assumed increased recurrence risk should the complex not be removed
• Studies have shown that malignant involvement of an areola/nipple to be present in 5%-43% of mastectomy specimens

None of the studies separate the respective involvement of the nipple versus the areola.

• Retrospective analysis 217 mastectomy specimens for nipple or areola involvement separately
• Nipple involvement 6% - 27% of patients
• Areolar involvement in <1% of patients – 0% DCIS – 0% invasive tumors <5cm – 0% tumors away from retro-areolar area

Simmons, Annals of Surgical Oncology, 2002

The Next Step: Areolar-Sparing Mastectomy

• Selected patients will be offered to spare the areola with removal of only the nipple: – DCIS – Prophylactic mastectomies – ?distal small invasive cancers

Converting a complicated outcome into a good reconstruction Werner P. Audretsch, M.D., Chief Dept. of Breast Surgery, Metropolitan Hospital, Dusseldorf, Germany

Classification
COMPLICATED RESULTS after breast surgery are related to the diagnosis, volume of resection, location of the lesion, the type an method of the surgical technique, the volume of the breast and the experience of the surgeon and his surgical skill. Other risk factors are the physical conditions of the patient, age, weight, diabetes and smoking.

Problem
It remains difficult to provide precise numbers of the extension and specific incidence rates on the diverging data in the literature. In addition the spectrum of surgical interventions of the breast was enlarged during the last decades and has enabled the occurrence of new problems. The indication for breast conserving surgery have increased after neo-adjuvant treatment. The aesthetic results after true quadrantectomy need revision in 20% of cases and are limited particularly with small breasts in 90%. Therefore, the factors of unfavourable relative size and unfavourable site belong to the relative contraindications of breast conservative treatment.The results of the EORTC-10801- Study show that there is basically no oncological contraindication for BCT because of tumor size or involvement of the lymph nodes alone. There is a growing number of different implant and autologous procedures of breast reconstruction. In the same way more functional techniques of breast cancer surgery and for for the axilla i.e. sentinel lymphe node biopsy are gaining importance. A specific aspect of breast surgery is the fact that a reduced cosmetic outcome counts for a complication.

Diagnosis

The assessment is based on esthetic principles of the breast:

• size
• shape
• symmetry

Etiology

• wrong technique (implant, autologous, combination)
• wrong patient (indication, sequence to other treatment)
• wrong doctor (experience, specific training, lack of interdisciplinary approach)

Due to the implicit oncological point of surgery for breast cancer , plastic and reconstructive surgery requires considerations of treatment sequence for CHT and radiotherapy. However, an immediate reconstruction cannot be performed without a meticulous preoperative evaluation of the cancer status and an upfront planning during the treatment conference.

Treatment
Autologous local tissue or transferred tissue can be used to cover defects or to convert a failed implant reconstruction. Local tissue is used, for example, in cases of defect shrinking achieved through different volume reduction techniques i.e. reduction mammoplasty, and mastopexy techniques involving different defect-adapted skin patterns such as the standard key-hole pattern, the modified “B” technique developed by Regnault and applied to central and inner-lower pole lesions, the oblique pattern, the “purse-string” pattern , the inverted “T”-pattern for low-pole lesions, and the inverted Rubin pattern preferred for other kinds of defect location in large or pendulous breasts. A thoraco-epigastric flap (TEF) or thoraco-dorsal flap (TDF) may be recommendable for reconfiguring the infero-medial and infero-lateral aspect of the breast. Local autologous tissue is taken from the area adjacent to the tumor bed or the chest wall and should be radiated after surgery in cases of breast-conserving treatment.

Distant and transferred autologous tissue is used in partial or total mastectomy reconstruction on behalf of a myocutaneous latissimus dorsi flap (LAT) for lesions in the unfavourable borderline of the breast and for relative size problems or together with an implant. This kind of tissue is reliable as long as the thoraco-dorsal pedical and/or the serratus branch remains intact. Because of its twofold (either simultaneous or successive) availability and its paired occurrence, in which it resembles the breast, the most important and best suited “work horse” for the coupled surgical approach as well as for volume (i.e. “mini-flap”) and skin replacement is the myocutaneous latissimus dorsi island flap. The evolution of the latiss from the safest tool in delayed post radiation repair surgery or deformities to the mainstay in cases of reconstruction after partial or total mastectomy with regard to new treatment protocols represents a breakthrough in the field of breast cancer surgery. The decision between partial and total mastectomy operability is brought about solely by the distribution of the tumor in the breast. The myocutaneous rectus flap (TRAM) has become the state of the art in total mastectomy reconstruction. Looked at from this point of view, coupled reconstructive surgery is able to facilitate mastectomy operability as well or to support a delayed salvage surgery.

Transferred tissue is generally considered healthy and free from tumor cells. Generally, radiotherapy is not indicated from an oncological point of view and therefore be applied prior to surgery. In individual cases radiotherapy can also take place after latissimus partial or total mastectomy reconstruction but not recommended after TRAM-flap reconstruction. A simpler reconfiguration can follow by means of mirror biopsy. The preference of bilateral surgery for Q.U.A.R.T. and of the recentralization of the N.A.-complex was based on the aim of restoring symmetry after quadrantectomy or, in cases of asymmetry, of favouring the non-affected breast.In most of the cases the basis of the breast is narrowed. This results in a decentralization and, most frequently, in a lateralization of the N.A.-complex. Consequently, recentralization should be performed by means of a peri-areolar concentric mastopexy, i.e. the “purse string” technique.

A response-dependent indication for larger plastic intervention with the aim of creating a tumor cell free operative zone is desirable.

Prevention
In view of the fact that adjuvant to oncological surgery, radiotherapy, and chemotherapy, plastic and reconstructive surgery becomes increasingly integrated into the comprehensive management of breast cancer, it goes without saying that breast reconstruction in general and above all coupled procedures require an even more sophisticated and detailed pre-treatment planning and sequencing. Moreover, sophisticated integration of plastic surgery together with modern implants, autologous tissue and the approach of onco-plastic surgery may resource costs and help to save money because of the aim of predictable or a one-step procedure, fewer re-excision problems, non-delayed reconstructions, avoidance of secondary surgery and complications after partial and total mastectomy, and involves well indicated or fewer contralateral procedures as in most cases it is a natural breast that is reconstructed.

Sequence of endocrine therapy for metastatic breast cancer in pre- and postmenopausal women C. Kent Osborne, M.D., Professor of Medicine & Cell Biology, Baylor College of Medicine, Houston, TX

Endocrine therapy can be classified according to its mechanism of action. These include therapies designed to reduce the estrogen level, selective estrogen receptor modulators such as tamoxifen that have partial agonist activity, ER downregulators and pure antiestrogens such as Faslodex, and the pharmacologic administration of estrogens, androgens, and progestins. In postmenopausal women there is now considerable evidence demonstrating that aromatase inhibitors are superior to tamoxifen as first line therapy for metastatic breast cancer. Both Faslodex and the aromatase inhibitors are effective in patients resistant to tamoxifen, and Faslodex has been shown to be at least as effective as Arimidex in this setting. Aromatase inhibitors may be particularly more effective than tamoxifen in tumors that overexpress the HER-2 oncogene. In premenopausal patients ovarian ablation by surgery or through LHRH agonists remains effective treatment, as does the antiestrogen tamoxifen. Some data suggest that the combination of ovarian ablation plus tamoxifen is superior to either agent alone. Aromatase inhibitors are not effective in premenopausal women with functioning ovaries, but they can be considered in patients who have had prior ovarian ablation. Faslodex also has not been studied in premenopausal patients, but it can also be considered in those who have lost ovarian function. The optimal sequence of endocrine therapy has not been carefully defined, especially considering the new agents now available. One strategy in premenopausal patients would be to be to consider ovarian ablation with or without tamoxifen as initial therapy with aromatase inhibitors or Faslodex as second and third line treatments. In postmenopausal women, aromatase inhibitors or even still tamoxifen can be considered initial treatment with the alternative or Faslodex reserved for secondary and tertiary treatment. Pharmacologic treatment with high doses of estrogens, androgens, or progestins is reserved for fourth and fif th line treatment. Using these sequences of endocrine therapy many patients can be controlled for years before requiring more aggressive and toxic cytotoxic chemotherapy.

Choice of Cytotoxic Regimen: Single vs Combination, Sequential vs Combination, Dose-Density vs High Dose Clifford Hudis, M.D., Chief, Medical Oncology of Breast Center, Memorial Sloan-Kettering Cancer Center, New York City, NY

The meta-analyses performed by the Early Breast Cancer Trialists’ Collaborative Group clearly demonstrate that combination chemotherapy in the adjuvant setting significantly reduces the risks of relapse and, to a lesser extent, death. The three drug combination comprising CMF given for about 6 months represents a gold standard but it is likely that other regimens will be found to be consistently superior.

Clinical research in recent years has focused on the use of dose-escalated therapy and the role of new active drugs, such as anthracylines, taxanes, and others. Despite pre-clinical models suggesting significant benefits to dose-escalation and intensity as well as a large number of promising phase II studies, a clear and consistent benefit for higher dose therapy has not been seen, especially when considering dose levels significantly above standard. As a result high dose therapy appropriately remains investigational. Alternative means of increasing chemotherapy effect include the use of dense treatment plans designed to overcome resistance by increasing the exposure of tumor cells to drug and the incorporation of new active agents.

Dose-Escalation
Laboratory evidence for a steep dose to response relationship, in particular for alkylating agents, initially led to numerous feasibility and pilot trials testing the use of very high dose treatments in patients. To support patients through these treatments autologous stem cells, collected from the marrow or, more recently, peripherally, were harvested and re-infused following the high dose treatment. Because kinetic models of tumor growth and chemotherapy response suggested that the greatest likelihood for cure would be in the minimal tumor burden situation, patients with high risk early stage disease were considered an ideal testing ground for this approach. Promising non-randomized results allowed high dose adjuvant chemotherapy to become very popular even before prospective randomized data was available. Now, however, there have been three such studies published in manuscript form and several more as abstracts only and, while one can not rule out a benefit for this approach, the available results do not demonstrate a significant benefit. Additional disappointment was negative seen in the results of studies testing dose escalation for cyclophosphamide above 600 mg/m2 from the NSABP trials B22 and B25 and another testing doxorubicin dose-escalation above 60 mg/m2 in the recent CALGB trial (9344). For all of these reasons, clinicians should remain cautious regarding the use of maximally dose-escalated therapy outside of properly conducted prospectively randomized trials unless and until there is clearer evidence of their benefit.

Dose Dense Chemotherapy Regimens
Dose-intensity quantifies the total amount of drug administered over a specified period of time and expresses it in terms of milligrams per meter-squared per week. Increases in dose-intensity are therefore possible not only by increasing dose size (dose-escalation) but also by decreasing the interval between treatments (shortening the time period). The latter method for dose-intensification, first proposed by Norton and Simon, can be labeled “dose-dense” treatment to distinguish it from all other dose-intensification schemas. A trial conducted in Milan and enrolling women with 4 or more involved nodes was one of the best tests of dose-dense therapy. Here treatment consisted of alternating (less dose-dense) versus a sequential (more dose-dense) regimens using single agent doxorubicin (A) and CMF and over 33 weeks of treatment every patient on the study received 4 doses of doxorubicin and 8 of CMF. With 10 years of follow-up the sequential plan consisting of 4 cycles of doxorubicin followed by 8 of CMF was associated with a significant improvement in disease-free and overall survival compared to the alternating one. Based on these results plus those of several promising pilot trials the North American Intergroup conducted several trials where dose-density was the critical question. One study compared concurrent AC versus sequential (more dose-dense) administration of the same cumulative doses of these drugs, another compares every other week chemotherapy with every third week treatment, and yet another compares a dose-dense regimen versus a “conventional” high dose therapy approach consisting of AC followed by a single cycle of high dose therapy. Results from these randomized studies are awaited.

Taxanes: Update on use in adjuvant and metastatic setting I. Craig Henderson, M.D., Adjunct Professor of Medicine, University of California, San Francisco, CA

The taxanes (along with new synthetic vincas, such as vinorelbine) have proven to be among the most active agents in the treatment of breast cancer. Most recently paclitaxel has been evaluated in the adjuvant setting in three randomized trials. Results from Intergroup trial 9344 have been reported several times with consistent results. There is a statistically significant improvement in both disease-free and overall survival that appeared by the 1st year of follow-up. However, an unplanned subset analysis of this study demonstrated that all or almost all of the benefit was seen among those patients who had receptor negative tumors and did not receive tamoxifen. The reduction in the hazard of recurrence over six years in the ER negative group is 29% greater than that achieved with 4 cycles of cyclophosphamide and doxorubicin (CA) alone. NSABP B-28 was of a similar size and design as 9344. The trials differed primarily in the mix of patients enrolled, the use of tamoxifen in a larger proportion of the NSABP patients, and the use of a higher dose of paclitaxel by the NSABP. Preliminar y data were presented at the NIH consensus conference. In the population as a whole, no significant benefits were observed in the group that received paclitaxel, but a differential effect of paclitaxel was seen between those who had ER positive tumors and received tamoxifen and those with ER negative tumors, just as in trial 9344. However, in the NSABP study the 14% reduction in hazard of recurrence for this group was not statistically significant. The results from both trials were confounded by the fact that those randomized to the paclitaxel arm of the study received 6 months of therapy while those given only CA had only 3 months. A smaller randomized trial in which the duration of therapy was constant in both arms was conducted by M.D. Anderson. This study demonstrated a benefit from using paclitaxel, but the number of events available from this study were too few to reliably detect a benefit of the size seen in trial 9344. Important questions about the use of taxanes are currently under evaluation by the cooperative groups. These include the relative efficacy of paclitaxel and docetaxel and the ideal dose-schedule, weekly or every 3 weeks.

Herceptin as single agent and/or combination with cytotoxic or hormonal agents Debu Tripathy, M.D., UCSF Carol Franc Buck Breast Care Center, University of California, San Francisco, CA

The neu oncogene was initially identified over 20 years ago in rat carcinogen-induced neural tumors. The human homologue of this gene, HER2/neu, encodes a transmembrane tyrosine kinase receptor, which belongs to a family of receptors that are involved in numerous functions including embryological development and cell growth. Amplification of the HER2/neu gene and overexpression of the protein product was found to present in 20-30 percent of primary breast tumors and accompanied by a worse outcome, suggesting that this may represent a potential therapeutic target. Monoclonal antibodies to HER2/neu were shown to inhibit HER2/neu-expressing breast cancer cells and to act synergistically with certain chemotherapies such as taxanes and platinum agents. A humanized anti-HER2 antibody, Herceptin, has now been tested in small and larger clinical trials and demonstrated activity as shown below:

Table 1 - Phase II trials Herceptin for Breast cancer

a Herceptin was given as a loading dose of 4 mg/kg followed by 2 mg/kg intravenously every week
b Patients were randomized to 4 mg/kg followed by 2 mg/kg intravenously every week vs 8 mg/kg followed by 4 mg/kg every week

Table 2 Randomized Trial of Chemotherapy vs. Chemotherapy plus Herceptin

AC= Anthracycline plus cyclophosphamide

Thus, this biologically targeted therapy is one of the few that have been shown to improve survival in metastatic breast cancer. However, cardiomyopathy, which is felt to be due to modulation of HER2-mediated signaling in myocytes has been observed, especially in combination with anthracyclines. Otherwise, therapy is generally well tolerated. Herceptin is currently indicated in combination with paclitaxel for first line therapy of HER2-positive metastatic breast cancer and as a single agent for refractory disease. Clinical trials have shown promising results with Herceptin in combinations with other agents such as weekly paclitaxel and vinorelbine. Other agents and hormonal combinations are also being studied.

The optimal way to determine HER2/neu tumor status and likelihood of response to Herceptin remains somewhat controversial. Immunohistochemical staining may be falsely negative due to tissue fixation but can also be falsely positive. Direct analysis of gene amplification using fluorescence in situ hybridization (FISH) may allow for a more accurate assessment of HER2 status and for better patient selection. Additionally, many patients with truly HER2-positive tumors do not respond to Herceptin for reasons that are not known, and there is active research ongoing to identify protein and genetic markers that will better predict responsiveness to therapy.

Currently, large multi-center trials are ongoing for patient with early stage breast cancer in both Europe and the United States. In general, eligible patients have HER2-positive tumors (3+ by immunohistochemical staining or positive by FISH) and positive axillary nodes. Most trials are using anthracycline and cyclophosphamide therapy followed by a taxane given with or without Herceptin and one trial is also testing Herceptin with a platinum agent and a taxane. In these trials, the benefit would need to exceed any cardiotoxicity, so very close monitoring for these events is planned. Detailed centralized tissue testing is also built in so that further correlations between tissue markers and clinical benefit can be made.

References

Shih C, Padhy LC, Murray M, et al. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:26l, l98l.

Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:l77, l987.

Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2/neu monoclonal antibody in patients with HER2/neu overexpressing metastatic breast cancer. J Clin Oncol 14:737, 1996.

Cobleigh M, Vogel C, Tripathy D, et al. Multinational study of efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639, 1999.

Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783, 2001.

Seidman AD; Fornier MN; Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19:2587-95.

Burstein HJ, Kuter I, Campos SM et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001; 19:2722-30.

Microdissected breast cancer biopsied before, during and after Hereptin and Taxol therapy Emmanuel Petricoin, M.D., Co-Director, FDA-NCI Clinical Proteomics Program, Bethesda, MD

While the underlying cause of human cancer lies mainly within multiple genetic mutations, at a functional level cancer is a proteomic disease. Derangements in signal pathway activation, the cellular “circuitry”, ultimately underpin aberrant cellular growth and metastasis. However, the exact identification of the rewiring of the protein network has never been elucidated in actual human cancer cells in tissue, with most information being gleaned in cell culture and animal model studies. Treatment with new classes of molecular targeted therapeutics such as IRESSA(r), GLEEVEC(r) or HERCEPTIN(r), requires the presence of over-expressed receptors or activated signaling molecules for therapeutic success. Ultimately, realization for a future in which true patient-tailored therapy is realized will rely on new proteomic approaches to discover the states of signal pathway activation within the patients tumor, and the effect of therapy not just on the proposed target but also on the pathway in which the target resides. We therefore employed Laser Capture Microdissection obtain an in vivo pattern of pathway activation within cancer cases that revealed patient-specific activation patterns regardless of over-expression and activation of c-ErbB2. Our analysis in primary tissue highlights the complexity of cellular signaling that occurs within human cancer cells and underscores the importance of phosphoprotein screening in clinical diagnostics. Finally, we extend our analysis to multiplexed signal pathway profiling in human biopsy material obtained from patients before, during and after HERCEPTIN(r) treatment and show the Akt pro-survival pathway is repressed in the treated samples.

Capecitabine: lessons learned and future directions Kathy D. Miller, M.D., Associate Professor of Medicine, Indiana University, Indianapolis, IN

Capecitabine is an oral fluoropyrimidine prodrug activated by a three-step metabolic process to 5-fluorouracil. As malignant tissue typical has higher thymidine phosphorylase activity, the end result is higher concentrations of 5-fluorouracil in tumor relative to surrounding normal tissue. In a multicenter phase II trial, objective responses were seen in 20% of patients who had had prior anthracycline- and taxane-based therapy leading to FDA approval. Side effects are similar to infusional 5-FU with diarrhea and hand-foot syndrome being the most frequent; myelosuppression and alopecia are uncommon. Combination with several existing agents is being explored. Recent exploration of alternate doses and schedules have limited toxicity and increased the use of this important agent. Two adjuvant trials including capecitabine are planned.

Taxotere + Xeloda in Metastatic Breast Cancer (MBC) Stephen E. Jones, M.D., Baylor-Sammons Cancer Center, Dallas, Texas, and US Oncology Research, Houston, TX

Background and rationale
There are many treatments for MBC including a variety of chemotherapeutic agents, most often employed as single agents. These include the taxanes, capecitabine (Xeloda), Navelbine and others. The goals of treatment are palliation and if possible prolongation of life. Two of the commonly used drugs are Taxotere and Xeloda, the latter of which is a prodrug, converted to 5-FU in tumor tissue by the enzyme thymidine phosphorylase (TP). TP is upregulated by the taxanes so there is a strong indication to evaluate the 2 agents together in MBC.

In the largest phase II study of Xeloda in 163 patients with MBC, the objective response (ORR) rate was 20% and 43% had stable disease.(1) With respect to Taxotere in MBC, response rates as high as 60% have been reported. In a randomized trial against doxorubicin Taxotere, produced an ORR of 48% compared to 33% for doxorubicin (p=0.008) as well as longer overall survival (OS).(2) Study Plan: The above rationale led to a randomized phase III trial of Taxotere (100 mgs/m2 IV q 3 weeks) versus Taxotere (75 mgs/m2 IV q 3 weeks) plus oral Xeloda (1250 mgs/m2 BID days 1-14) every 3 weeks in patients with MBC.

The results are summarized below: (3)

Toxicity in this study will be described. The results of this study led to FDA approval in 2001 of this XT regimen for patients with MBC.

References

1. Blum et al JCO 17:485, 1999.
2. Chan et al JCO 17:2341, 1999.
3. O’Shaughnessy et al, SABCS 2000 and JCO (in press, 2002).

New Drug Developments Daniel Hayes, M.D., Associate Professor of Medicine, Georgetown University Medical Center, Washington, DC

Over the last decade, several new drugs have been approved for treatment of breast cancer. These fall into four categories (bisphosphonates: pamidrondate; chemotherapy: capecitabine, epirubicin, paclitaxel, docetaxel; hormone therapy: anastrazole, exemestane, goserelin, letrozole, tamoxifen (new indications: DCIS, prevention), toremifene; and anti-HER2 therapy (trastuzumab). Several other new drugs have activity against breast cancer and have been commonly incorporated into treatment in the metastatic setting (liposomal doxorubicin, gemcitabine, vinorelbine).

Several new approaches have been and are being studied now. These include, broadly, EGFR family tyrosine kinase inhibitors (iressa, CI1033, others), anti-angiogenic agents (anti-VEGF, VEGF-r tyrosine kinase inhibitor, TNP470, MMPIs, others), anti-proliferative agents (CCI 779, others), and immunotherapeutic approaches. Another broad class of agents includes the anti-sense oligonucleotidcs (ASO). ASO against PKC and against bcl-2 are both in clinical trials. Each of these is in phase I or II trials now. Of these, anti-VEGF appears to be the most promising in terms of currently available data and the status of its development.

A major issue is phase II trial design. Obviously, major responses do not require new designs, but many of these agents may be more “cytostatic” and may not induce responses. Therefore, classic Phase II trial designs will result in false positive results. Newer Phase II trial designs use either “failure to progress” and/or surrogate biomarkers as endpoints to indicated some element of activity.

Back | Top of Page