European Journal of
Nuclear Medicine
Editorial
The prospects for imaging lymph nodes in breast cancer S.M. A l l a n The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
Breast cancer is extremely common in the Western World and is becoming increasingly so. At present, 1 woman in 10 will have breast cancer during her lifetime. Despite our advances in diagnostic technology, methods of treatment and understanding of the disease processes, little impact has been made on overall survival in the past 10 years (Canellos et al. 1982). Current treatment modalities are surgery, chemotherapy and radiotherapy. The usual treatment is a combination of some or all of these modalities. The prevention of the development of metastatic disease is the only method of improving the survival of patients with this disease, since once metastatic disease has become established in a patient, the therapeutic goals change from aiming for cure to those of palliation. Targetting those patients with either occult metastases or the potential for developing metastases in the future course of the disease to receive maximal therapy and at the same time restricting levels of therapeutic endeavour for those with essentially localised disease will satisfy both the cost-benefit analysis of their treatment and at the same time enhance overall survival figures. Information about the primary tumour is provided by mammography, ultrasound, fine needle aspiration cytology, histology and assessment of biological disease markers. None of the results provided by these tests has great prognostic significance by itself, but in combination they provide the ability to predict the patient's increasing likelihood of developing metastases. The single most important predictive factor comes not from the study of the breast primary tumour but from the state of the regional lymph nodes (Fisher 1986). At presentation, if the axillary nodes are found to have metastatic turnout, this is by far the best indicator of the biological characteristics of the breast cancer. Whilst lymph node metastases do not predict direct disease extension, they do show the ability of the primary tumour to develop distant metastases. Although information from the primary tumour will continue to be obtained, despite recent minimalist thinking, it would be preferable to obtain information regarding the lymph node status without recourse to surgery. In the management of patients with metastatic disease of the axillary nodes, surgery would then have solely therapeutic rather than diagnostic aims. If the assessment of the lymph node status is to have maximum predictive power, both axillary and internal
mammary nodes should be imaged. Although 70% of patients with involved axillary nodes also have involvement of the internal mammary nodes, a further 6% will have metastatic disease in the internal mammary nodes without any evidence of disease in the axillae (Handley 1975). This could well explain why some of the "nodenegative patients" on axillary staging procedures behave as node-positive in their disease course unless maximally treated. A full assessment of all the regional nodes is the only way an impact on survival may be obtained without giving all patients maximum therapy, but this assessment must be done by an imaging method to avoid the retrograde step of extra surgery. To this end, conventional radiology in the form of ultrasound and computerised tomography have been tried and largely failed as routine methods of detecting disease in the axillae due to a lack of definition of the smaller nodes and the inability to differentiate reactive from metastatic changes. The role of Doppler ultrasound and magnetic resonance imaging are currently being investigated. Lymphoscintigraphy with radiolabelled colloids has similarly been tried but has had problems with non-specific uptake and lack of uptake in nodes replaced with tumour. Delivery of the colloids to the regions of interest with alternative routes of administration (directly or indirectly into the lymphatics) have also been tried (McLean and Ege 1986). The problem of disease specificity is best addressed by using a monoclonal antibody instead of an inert colloid, thus creating a biologically targeted system. Many of the vascular barrier and delivery problems associated with antibody imaging can be improved by using a non-chelating method of radiolabelling, thus reducing the molecular size of the conjugate. Earlier studies with radioimmunoscintigraphy (RIS) mostly relied on using a single monoclonal antibody for all types of breast tumour and employed isotopes with relatively long half-lives (iodine-131, indium-111) to allow maximum acquisition of the antibody by the antigen (Larson 1990; Tjandra et al. 1989). Now that Schwarz has shown that reduction methods of labelling with technetium-99m will produce a better labelling efficiency whilst preserving immunoreactivity (Schwarz and Steinstraesser 1987), the better imaging characteristics of 99rnTC outweigh the potential problems produced by its short half-life. As long as at the time of imaging suffiEur J Nucl Med (1992) 19:836-837
© Springer-Verlag 1992
837
cient activity remains to permit acquisition of the data, and sufficient time has elapsed for the antibody to bind to the antigens on the tumour, the 6-h half-life poses no real problems. In addition, the fact that the isotope no longer hangs off the antibody as a chelated label but is hidden within the antibody structure improves its ability to reach the tumour from the vascular compartment. More than adequate images are obtainable at 24 h after injection, with good levels of activity being shown by the turnout. Whilst other short half-life isotopes such a s 124I are extremely interesting from a research point of view, the paucity of position emission tomography (PET) scanners and a lack of 124I availability will limit their general usage and commercial viability. With the introduction of a technique of duplicating information from a single fine-needle aspiration by cytospinning the specimen, we have the ability to pretest the individual patient's primary turnout against a panel of suitable antibodies using an immunocytochemical technique. Thus, the optimum antibody can be selected for each individual patient's primary tumour antigens, and this antibody can then be radiolabelled with 99mTc for the imaging studies. The previous problems of heterogeneity of tumour expression of the antigen, non-specific uptake by normal tissues and circulating antigens in the blood are therefore neatly circumvented. The future prospects of imaging the tumour in lymph nodes in breast cancer patients rely on the adaptation of existing techniques of RIS, the development of a satisfactory bank of antibodies and using RIS in conjunction with either Doppler ultrasound or magnetic resonance
imaging. A combination of these techniques should replace axillary surgery for diagnostic purposes and reserve its place as a potential therapeutic modality for local disease control only. With these adaptations the early promise of RIS can come to fruition, and nuclear medicine will have an important role in providing a more logical approach to the future diagnosis and management of breast cancer.
References Canellos GP, Hellman S, Veronesi U (1982) The management of early breast cancer. N Engl J Med 306:1430 1432 Fisher ER (1986) Prognostic and therapeutic significance of pathological features of breast cancer. Natl Cancer Inst Monograph 1:29-34 Handley RS (1975) Carcinoma of the breast. Ann Royal Coll Surg Engl 57:59 66 Larson SM (1990) Clinical radioimmunodetection 1978-1988: overview and suggestions for standardisation of clinical trials. Cancer Res [Suppl] 50 : 892s-898s McLean RG, Ege GN (1986) Prognostic value of axillary lymphoscintography in breast cancer patients. J Nucl Med 27:11161124 Schwarz A, Steinstraesser A (1987) A novel approach to technetium 99m labelled monoclonat antibodies (abstr 695). J Nucl Med 28 : 721 Tjandra JJ, Sacks NPM, Thompson CH, et al. (1989) The detection of axillary lymph node metastases from breast cancer by radiolabelled monoclonal antibodies : a prospective study. Br J Cancer 59:296-302
Nuclear Medicine
Editorial
The prospects for imaging lymph nodes in breast cancer S.M. A l l a n The Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK
Breast cancer is extremely common in the Western World and is becoming increasingly so. At present, 1 woman in 10 will have breast cancer during her lifetime. Despite our advances in diagnostic technology, methods of treatment and understanding of the disease processes, little impact has been made on overall survival in the past 10 years (Canellos et al. 1982). Current treatment modalities are surgery, chemotherapy and radiotherapy. The usual treatment is a combination of some or all of these modalities. The prevention of the development of metastatic disease is the only method of improving the survival of patients with this disease, since once metastatic disease has become established in a patient, the therapeutic goals change from aiming for cure to those of palliation. Targetting those patients with either occult metastases or the potential for developing metastases in the future course of the disease to receive maximal therapy and at the same time restricting levels of therapeutic endeavour for those with essentially localised disease will satisfy both the cost-benefit analysis of their treatment and at the same time enhance overall survival figures. Information about the primary tumour is provided by mammography, ultrasound, fine needle aspiration cytology, histology and assessment of biological disease markers. None of the results provided by these tests has great prognostic significance by itself, but in combination they provide the ability to predict the patient's increasing likelihood of developing metastases. The single most important predictive factor comes not from the study of the breast primary tumour but from the state of the regional lymph nodes (Fisher 1986). At presentation, if the axillary nodes are found to have metastatic turnout, this is by far the best indicator of the biological characteristics of the breast cancer. Whilst lymph node metastases do not predict direct disease extension, they do show the ability of the primary tumour to develop distant metastases. Although information from the primary tumour will continue to be obtained, despite recent minimalist thinking, it would be preferable to obtain information regarding the lymph node status without recourse to surgery. In the management of patients with metastatic disease of the axillary nodes, surgery would then have solely therapeutic rather than diagnostic aims. If the assessment of the lymph node status is to have maximum predictive power, both axillary and internal
mammary nodes should be imaged. Although 70% of patients with involved axillary nodes also have involvement of the internal mammary nodes, a further 6% will have metastatic disease in the internal mammary nodes without any evidence of disease in the axillae (Handley 1975). This could well explain why some of the "nodenegative patients" on axillary staging procedures behave as node-positive in their disease course unless maximally treated. A full assessment of all the regional nodes is the only way an impact on survival may be obtained without giving all patients maximum therapy, but this assessment must be done by an imaging method to avoid the retrograde step of extra surgery. To this end, conventional radiology in the form of ultrasound and computerised tomography have been tried and largely failed as routine methods of detecting disease in the axillae due to a lack of definition of the smaller nodes and the inability to differentiate reactive from metastatic changes. The role of Doppler ultrasound and magnetic resonance imaging are currently being investigated. Lymphoscintigraphy with radiolabelled colloids has similarly been tried but has had problems with non-specific uptake and lack of uptake in nodes replaced with tumour. Delivery of the colloids to the regions of interest with alternative routes of administration (directly or indirectly into the lymphatics) have also been tried (McLean and Ege 1986). The problem of disease specificity is best addressed by using a monoclonal antibody instead of an inert colloid, thus creating a biologically targeted system. Many of the vascular barrier and delivery problems associated with antibody imaging can be improved by using a non-chelating method of radiolabelling, thus reducing the molecular size of the conjugate. Earlier studies with radioimmunoscintigraphy (RIS) mostly relied on using a single monoclonal antibody for all types of breast tumour and employed isotopes with relatively long half-lives (iodine-131, indium-111) to allow maximum acquisition of the antibody by the antigen (Larson 1990; Tjandra et al. 1989). Now that Schwarz has shown that reduction methods of labelling with technetium-99m will produce a better labelling efficiency whilst preserving immunoreactivity (Schwarz and Steinstraesser 1987), the better imaging characteristics of 99rnTC outweigh the potential problems produced by its short half-life. As long as at the time of imaging suffiEur J Nucl Med (1992) 19:836-837
© Springer-Verlag 1992
837
cient activity remains to permit acquisition of the data, and sufficient time has elapsed for the antibody to bind to the antigens on the tumour, the 6-h half-life poses no real problems. In addition, the fact that the isotope no longer hangs off the antibody as a chelated label but is hidden within the antibody structure improves its ability to reach the tumour from the vascular compartment. More than adequate images are obtainable at 24 h after injection, with good levels of activity being shown by the turnout. Whilst other short half-life isotopes such a s 124I are extremely interesting from a research point of view, the paucity of position emission tomography (PET) scanners and a lack of 124I availability will limit their general usage and commercial viability. With the introduction of a technique of duplicating information from a single fine-needle aspiration by cytospinning the specimen, we have the ability to pretest the individual patient's primary turnout against a panel of suitable antibodies using an immunocytochemical technique. Thus, the optimum antibody can be selected for each individual patient's primary tumour antigens, and this antibody can then be radiolabelled with 99mTc for the imaging studies. The previous problems of heterogeneity of tumour expression of the antigen, non-specific uptake by normal tissues and circulating antigens in the blood are therefore neatly circumvented. The future prospects of imaging the tumour in lymph nodes in breast cancer patients rely on the adaptation of existing techniques of RIS, the development of a satisfactory bank of antibodies and using RIS in conjunction with either Doppler ultrasound or magnetic resonance
imaging. A combination of these techniques should replace axillary surgery for diagnostic purposes and reserve its place as a potential therapeutic modality for local disease control only. With these adaptations the early promise of RIS can come to fruition, and nuclear medicine will have an important role in providing a more logical approach to the future diagnosis and management of breast cancer.
References Canellos GP, Hellman S, Veronesi U (1982) The management of early breast cancer. N Engl J Med 306:1430 1432 Fisher ER (1986) Prognostic and therapeutic significance of pathological features of breast cancer. Natl Cancer Inst Monograph 1:29-34 Handley RS (1975) Carcinoma of the breast. Ann Royal Coll Surg Engl 57:59 66 Larson SM (1990) Clinical radioimmunodetection 1978-1988: overview and suggestions for standardisation of clinical trials. Cancer Res [Suppl] 50 : 892s-898s McLean RG, Ege GN (1986) Prognostic value of axillary lymphoscintography in breast cancer patients. J Nucl Med 27:11161124 Schwarz A, Steinstraesser A (1987) A novel approach to technetium 99m labelled monoclonat antibodies (abstr 695). J Nucl Med 28 : 721 Tjandra JJ, Sacks NPM, Thompson CH, et al. (1989) The detection of axillary lymph node metastases from breast cancer by radiolabelled monoclonal antibodies : a prospective study. Br J Cancer 59:296-302
