14

sponse of Laser-Irradiated Tissue. New York: Plenum Publishing Corp., 667-707.

Ramanujam, N., M. Follen Mitchell, A. Mahadevan- Jansen, S.L. Thomsen, G. Staerkel, A. Malpica, T. Wright, N. Atkinson, and R. Richards-Kortum. 1996. Cervical pre-cancer detection using a multivariate statis- tical algorithm based on laser induced fluorescence spec- tra at multiple excitation wavelengths. Photochemistry and Photobiology 6:720-35.

I I I Opportunit ies for Optical Diagnostic and Therapeut ic Methods for Breast Cancer

Cancer of the breast is one of the most common ma-

lignancies in the United States, with about 150,000 new cases diagnosed each year. One out of every eight

American women will develop breast cancer during her

life span, and mortality is second only to that from lung

cancer.

Current Standard Diagnostic Procedures: Limi- tations

As in all other malignancies, early detection is criti-

cal for effective treatment. Breast cancer diagnosis re- lies on conventional and novel modalities, including but not limited to:

• visual inspection and manual palpation

• conventional x-ray mammography

• digital x-ray mammography

• magnetic resonance imaging (MRI)

• ultrasound

• nuclear medicine/positron emission tomography (PET)

• biopsy

• lumpectomy or mastectomy.

Conventional, film-based x-ray mammography is of

critical importance to breast cancer screening, but there

are a number of disadvantages which must be kept in mind.

Breast malignancy diagnostics based on x-ray mam- mograms rely on the identification of microcalcifica-

tions, masses, architectural distortions, and density

variations. The microcalcifications often represent an

indirect sign of a tumor and are also seen in benign le-

sions. In some cases, in particular in aggressive cancer, the microcalcification may be the only visible sign on

the mammogram as this type of cancer appears with ar-

eas of necrosis, which may not generate any "shadows"

on the image.

Another indirect sign is architectural distortion,

which represents changes in the parenchyma, reflecting the tumor growth in the breast. The density variations

in the breast parenchyma can be a true sign of a malig-

nant tumor but may also represent fibroadenomatous tis-

sue of a benign nature. The utility of x-ray mammogra-

phy is particularly limited in younger women (40-49 years and younger) who have higher probability of

radiodense breast tissue.

In addition to the problems with the interpretations

of the conventional mammograms, there are other dis-

advantages. One major issue is the delivery of a low

dose of ionizing radiation in women carrying the ataxia-

telangiectasia (AT) gene. This gene is carried by about 1% of the population. It has been reported that the AT

gene 1 predisposes those carrying it to breast cancer. It

has also been shown that 9-18% of all persons with

breast cancer in the US are heterozygote carriers of the

AT gene. Findings have been reported supporting the

possibility that doses of ionizing radiation below 20

mGy might induce breast cancer in females carrying the

AT gene. The corresponding dose for females without

the AT gene is above 100 to 200 mGy.

Emerging Methods

The limitations of conventional mammography high-

light the importance of the emergence of ultrasound,

MRI, and other novel imaging modalities for the detec-

tion of breast cancer. Breast MRI equipment, however,

while very promising for detecting and staging of breast

cancer, is expensive and usually limited to major uni- versity hospitals. Although lower in resolution at the

present time, ultrasound is less expensive. The major

potential for ultrasound is the ability to differentiate

cyst formations from other types of lesions (e.g., solid abnormalities) in the breast parenchyma. In cases when

abnormalities are detected by ultrasound, this technol-

ogy can be used for guidance of needle biopsy.

Malignant breast tumor detection utilizing ultrasound

with standard resolution has limitations, however. A

small malignancy in the breast (<10 ram) may be diffi-

cult to visualize. Further, it is difficult to differentiate a

benign solid fibroadenoma from a malignant lesion.

Needle biopsy is frequently used to investigate pal-

pable tumors or tumors visualized with different kinds

of diagnostic procedures. The histologic investigation

performed on the tissues sampled through the needle is

$170

critical to differentiate benign from malignant disease. 2-3

If optical biopsy technology could be sensitive to a

larger tissue volume, a more reliable method of tissue

characterization and guidance of transdermal needle bi- opsy could be developed.

Although there are several different methods to de- tect and diagnose breast cancer, there are still patients

for whom detection is postponed due to false negative

results of the imaging procedures. A major group for whom improved diagnostic methods are of greatest im-

portance is younger women, who usually have dense breast parenchyma, and in particular those with a family history of breast cancer.

Therapeutic Procedures

Optical Technologies to Benefit Open Surgery

In recent years the therapeutic procedures for breast carcinoma have developed into less invasive surgical procedures. In most situations, the radical mastectomy

has gradually been replaced with breast conservation

(either sector resection or, in some cases, only lump- ectomy). With positive histologic analysis, a concomi- tant resection of the axillary lymph nodes is also per- formed. The clinical challenge in connection with breast-conservative surgical procedures is to identify tumor borders correctly for determining the excision

margins, Even when a positive diagnosis of a local

("nonmetastatic") disease has been established, a partial

resection or lumpectomy can be problematic for the sur- geon since establishing disease-free margins of excision can often be difficult with heterogeneous lesions. For example, there might be a single tumor with or without

sharp borders in conjunction with intraductal tumor growth. Often the procedure is placed"on hold" while the anesthetized patient and the surgeon await pathol- ogy results from histology on frozen sections. An in-

stant, in situ diagnostic optical probe, in addition to speeding up the process, may permit the surgeon to

check surrounding tissue areas or even accessible lymph

nodes. Thus, the surgical procedure could be performed interactively with real-time optical tissue characteriza-

tion.

Optical Technologies for Less Invasive Therapies

Mastectomy or wide local excision (lumpectomy) in-

evitably leave cosmetic defects, although this can often

be at least partly ameliorated by reconstructive surgery. There is considerable interest in developing techniques that may be able to destroy breast cancers under imag-

ing guidance without the need for open surgery, espe- cially if this means that there is no need for general an-

esthesia and the procedure can be done on an outpatient

basis instead of requiring hospital admission, with the associated cost savings. The possible image-guided treatment techniques include local heating (with micro- waves, radio-frequency heating or lasers), cryotherapy, brachytherapy (interstitial radiotherapy), photodynamic

therapy, and local drug injection. One optical technique considered to be promising is Interstitial Laser Photoco-

agulation (ILP).

The concept of ILP is simple and was first described by Bown in 1983. 4 One or more thin laser fibers are in-

serted into diseased tissue within solid organs through needles that are placed percutaneously under image guidance. The needles are then pulled back enough to leave the tip of the fiber in direct contact with the target tissue. Near-infrared laser light (wavelength 800- 830nm) is then passed down each fiber at low power

(typically 2-10W for 3-10 minutes) to gently coagulate the tissue, without ablation or carbonization. As the la- ser light is only emitted from the tip of the fiber (or for a short distance back from the tip in the case of diffuser fibers) there is no damage to the overlying tissues through which the needles and fibers pass other than the minor effect of the actual needle insertion, so that the biological effect is limited to the zones around the fiber tips. Although most of the preliminary studies of ILP

treatment of cancer have been for liver lesions, Bown's group has also begun investigating ILP for treating nonmetastatic focal breast lesions?

Photodynamic therapy (PDT) is an alternative treat- ment method that is also noteworthy because of its po- tential in treatment of breast cancer. PDT may be espe- cially valuable intra-operatively or post-operatively to

treat small areas of malignancy in the vicinity of an ex- cised tumor that were not readily detected and might not have been removed during surgery. It will be essential to carry out studies to determine the selectivity of new

PDT agents for malignant versus nonmalignant breast tissue.

Summary

Key research opportunities for optical technologies

to improve the diagnosis and treatment of breast cancer

lie in the following areas:

• For screening: to develop and test nonionizing, radiation-based diagnostics, including exploiting the

possibilities of

$171

- optical mammography based on pulsed or modu-

lated laser light, with a potential for deep tissue penetra-

tion

- ultrasound detection with enhanced resolution

- low-cost MRI equipment

• For diagnosis: to develop and employ optical

probes for real-time tissue characterization

- as a primary diagnostic procedure

- as a peri-operative procedure for enhancement of surgical precision, especially during breast-conservative

procedures

• For treatment: to develop and test less-invasive

methods

- interstitial laser photocoagulation

- photodynamic therapy

References

1 Swift, M., D. Morrell, R.B. Massey, and C.L. Chase. 1991. Incidence of cancer in 161 families affected by ataxia-te- langiectasia. New England Journal of Medicine. 325 (26): 1831-6.

a Willis, S.L., and I. Ramzy. 1995. Analysis of false results in a series of 835 fine-needle aspirates of breast lesions. Acta Cytologica 39:858-864.

3 Purasiri, P., et al. 1996. A novel diagnostic index for use in the breast clinic. J Royal College of Surgeons of Edinburgh 41:30-34.

4 Bown, S.G. 1983. Phototherapy of tumours. World J Surg 7:700-709.

5 Harries, S.A., Z. Amin, M.E. Smith, and S.G. Bown. 1994. Interstitial laser photocoagulation as a treatment for breast cancer. Br J Surg 81:1617-1619.

IV Opportunit ies for Optical Diagnostic and Therapeut ic Methods in Diseases of the Female Reproductive Tract

The intrinsic features of optical methods make them

a particularly powerful set of tools for examining and

treating the female reproductive tract. This is due to its

ease of access, presence of superficial lesions, well-un- derstood disease progression, and the urgent need for

more effective and less-invasive diagnostic and thera-

peutic interventiorls. In addition, optical methods can

be devised to substantially reduce the time interval be-

tween diagnosis and therapy, potentially reducing health

care costs and minimizing patient anxiety. We have identified five principal areas that should be considered

as high priority opportunities for optical methods.

These include: (1) cervical disease: minimally invasive

diagnosis and therapy; (2) dysfunctional uterine bleed-

ing: minimally invasive treatment; (3) ovarian cancer:

laparoscopic-based diagnosis and therapy of peritoneal

lesions; (4) genital warts: noninvasive photodynamic

treatment; and (5) fertility: optical micromanipulation of gametes to improve fertility. Promising findings

have been reported by the Biomedical Optics commu-

nity in each of these five areas. It is critical to support

basic research programs that will encourage new dis-

coveries and practical applications of optical methods in

these high-priority areas, as well as preliminary clinical

testing and, when appropriate, multi-center clinical tri-

als and innovative translational research studies. Ulti-

mately, we believe this strategy will substantially accel-

erate the acceptance and availability of promising emerging photomedicine methods. Specific recommen-

dations and background regarding each topic follow be-

low.

The Cervix

Background

The combination of modern screening methods with

increasingly effective treatment modalities has led to a dramatic reduction in mortality due to cervical cancer

over the past five decades. In the US, however, 15,700

new cervical cancer cases were diagnosed and 4,900

women succumbed to their disease in 1996. ~ Despite the significant decline in the incidence and mortality of in-

vasive cervical cancer, there has been an increase in the

incidence of cervical intraepithelial neoplasia (CIN), 2

reflecting both improved screening and detection meth- ods and a true increase in the incidence of precancerous

lesions of the cervix. The CIN terminology divided cer- vical cancer precursors into three groups: CIN I, II, III

corresponding to mild, moderate and severe (carcinoma in situ) dysplasia? Another commonly used terminology

invokes the terms low-grade squamous intraepithelial

lesion (L-SIL) for CIN I and high-grade SIL (H-SIL) for

CIN II and CIN III. 2 The mortality of cervical cancer is

estimated to rise by 20% in the next decade unless im- provements are made in current screening and detection techniques. 3

Opportunities for Diagnostics

Current screening techniques for CIN and invasive cervical cancer include the single or combined use of

exfoliative cytology (Pap- [Papanicolaou] smear) and

$172