Commentary (Goldenberg): Diagnostic Use of Radiolabeled Antibodies for Cancer

The development of cancer imaging with radiolabeled antibodies, or radioimmunodetection (RAID), has spanned at least 2 decades, if we begin dating this from the use of antibodies made against human tumor-associated antigens, such as oncofetal antigen markers (eg, carcinoembryonic antigen) [1-3]. The evolution of this technology has involved polyclonal and monoclonal antibodies, whole antibodies, and various fragments; iodine-131, iodine-123, indium-111, and technetium-99m as radionuclides; and planar and single-photon emission computed tomography (SPECT), as reviewed elsewhere [4-5].

More recently, the prospects for using radioimmunoconjugates in cancer therapy, or radioimmunotherapy (RAIT), are being better defined [6]. Yet, the utility of RAID in clinical oncology has not been established, which is related, in part, to the myriad of published results on imaging of different tumor types in different situations, with different agents and different end points. For this reason, the clear and concise report by Harrison and Tempero is a welcome contribution to the literature; the high quality of their review is probably due to the collaboration of an imager with a medical oncologist well-versed in the therapeutic applications of radiolabeled antibodies.

The evidence for the usefulness of different radiolabeled antibodies in different tumors and clinical situations is an important focus of this article, which also highlights the potential uses of RAID. But to guarantee this technology's future in the armamentarium of cancer detection and diagnostic agents and methods, we need to graduate from potential applications to proven contributions. This requires well-designed prospective trials that demonstrate the role of RAID alone and its complementarity with conventional diagnostic methods, as well as the impact of RAID on various aspects of cancer management, from initial diagnosis to assessment of therapeutic response. Being a more functional test of a malignancy, since RAID reveals an antigen-expressing, proliferating lesion, it should complement the traditional radiologic methods that depend solely on anatomy, which are less reliable for diagnosing true neoplasia.

RAID in Refractory Cancers

Many reviewers, particularly regulatory experts, often ask, why perform RAID to find additional tumor sites in patients with cancers refractory to therapy, since better assessment of disease extent may not incur a management change? I suppose that if these tumor types continue to be refractory to treatment in the future, this may be a reasonable pharmacoeconomic position (whatever that may mean). On the other hand, early diagnosis of recurrence or metastasis can result in a reasonable expectation of surgical salvage.

In the neoplasms that respond to therapy, even when disseminated (such as lymphomas), the identification of additional disease sites, especially following therapy, can have a profound effect on outcome and should thus affect management. Similarly, the less responsive tumors also need agents that permit accurate and complete staging, so that better stratified clinical trials with promising new therapies can be undertaken. Do we truly need to prove how RAID impacts the management of a highly malignant, lethal neoplasm before we approve its use to better define disease extent? So long as it is accurate in defining cancer sites, especially when they are occult, RAID serves a clinical need, and this need is directly related to the extent to which the neoplasm can be treated effectively.

Delay in Trials

Harrison and Tempero are correct in observing that the impact of these agents on patient survival or well-being has not been established, nor has their cost effectiveness in patient management. I am not as confident as the authors, however, that we may learn this as "more large-scale trials address these key points," since I do not see the prospects for such trials if the development and approval of such agents continue to be delayed in this country, despite early enthusiasm.

There are fewer RAID agents in phase III clinical trials today than would have been predicted just 5 years ago, especially for nononcologic diseases. Is this because of a failure of the agents to make important clinical contributions, or because of the hurdles blocking clinical development and commercialization? My own view is that both are partly responsible, and that the more unfortunate consequence may be a commensurate inhibition of the development of RAIT, which is the logical offspring of RAID and which, in practice, may be used in tandem with detection and imaging. The successful integration of one RAID agent into the workup and follow-up of patients with a specific cancer type may reverse this trend, and will surely spur our optimism for cancer detection and therapy with radiolabeled antibodies and their further modified constructs. This should then solidify the future of RAID and stimulate our efforts to improve and expand RAIT beyond its initial apparent success in lymphomas [7].

References:

1. Primus FJ, Wang RH, Goldenberg DM, et al: Localization of human GW-39 tumors in hamsters by radiolabeled heterospecific antibody to carcinoembryonic antigen. Cancer Res 33:2977-2982, 1973.

2. Goldenberg DM, Preston DF, Primus FJ, et al: Photoscan localization of GW-39 tumors in hamsters using radiolabeled anti-carcinoembryonic antigen immunoglobulin G. Cancer Res 34:1-9, 1974.

3. Goldenberg DM, DeLand F, Kim E, et al: Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. N Engl J Med 298:1384-1388, 1978.

4. Goldenberg DM (ed): Cancer Imaging with Radiolabeled Antibodies. Norwell, Massachusetts, Kluwer Academic Publishers, 1990.

5. Goldenberg DM, Larson SM: Radioimmunodetection in cancer identification. J Nucl Med 33:803-814, 1992.

6. Goldenberg DM (ed): Cancer Therapy with Radiolabeled Antibodies. Boca Raton, Florida, CRC Press, 1995.

7. Press OW, Eary JF, Appelbaum FR, et al: Radiolabeled antibody therapy of lymphoma, in DeVita VT, Hellman S, Rosenberg SA (eds): Biologic Therapy of Cancer, pp 1-13. Philadelphia, Lippincott Healthcare Publications, 1994.