Fast track — ArticlesPreoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial
Introduction
In 2006, 38 890 new cases of renal carcinoma in the USA, with an annual mortality of 12 840, were reported.1 Management of small renal tumours continues to change and now urologists need to incorporate new and important information as they plan surgery. Around 70% of renal cortical tumours are confined to the kidney and 30% present either with, or later develop, metastatic disease.2 The initial diagnosis of renal mass is usually made with ultrasound, CT, or MRI.2 Most cases (70%) are discovered incidentally during CT-imaging procedures for other purposes.2 The median tumour size is about 4 cm, well within safe limits for partial nephrectomy if technically feasible. We now know that around 20% of these masses are benign tumours (eg, oncocytoma and fat-poor angiomyolipoma), 25% are indolent tumours with limited metastatic potential (eg, papillary and chromophobe carcinoma), and 54% represent the more potentially malignant conventional clear-cell carcinoma that uncommonly achieves its metastatic potential at a size of 4 cm or less.3 For patients who have been surgically treated for localised renal cortical tumours, postoperative nomograms have been constructed that are effective in predicting long-term survival based on a combination of clinical and pathological features.4, 5 Although benign, indolent, and malignant renal cortical tumours can display growth over time, metastatic potential is intrinsic to the histological subtype. Around 90% of patients who present with, or later develop, metastatic renal cancer have the clear-cell histological subtype.6
Renal biopsy is rarely done for a localised kidney tumour because of inaccuracy and ineffectiveness in clinical management. Surgical removal is the treatment of choice in this situation, and partial nephrectomy provides equivalent tumour control to radical nephrectomy.7 Partial nephrectomy is a legitimate option for tumours up to 7 cm in size, especially if they are exophytic (ie, growing outward from an epithelial surface).8
G250 is a monoclonal antibody that has been shown in animal and human studies to bind to clear-cell renal cell carcinoma.9 A subsequent study using human samples revealed that the antigen target of G250 was an epitope of carbonic anhydrase IX.10 By immunohistology, carbonic anhydrase IX (CA-IX) is found in more than 94% of human clear-cell renal carcinomas.11, 12 A chimeric form of the antibody (designated cG250) has been generated to be less immunogenic. An intriguing feature of this antibody is its exceptionally avid targeting in renal cell carcinomas, with biopsy-based studies showing tumour uptake approaching 0·1 %/g, the highest recorded for any solid tumour.13 G250, in its murine and chimeric forms, has been used extensively as a potential therapeutic agent, either alone or conjugated with a radioactive isotope.14, 15, 16, 17, 18, 19 These earlier studies have also established that there is saturation of normal antigen sites in the liver at cG250 doses of 5 mg or more, and doses of 10 mg have been used in therapeutic studies.15, 16, 18
Because of its very high resolution and sensitivity20 and its unique ability to measure tissue concentrations of radioactivity in three dimensions, PET is the method of choice for in-vivo imaging of therapeutic and diagnostic antibodies. Iodine-124 (124I) is a positron emitter21 that can be attached to antibodies without loss of immunobiological characteristics; its 4-day half-life allows the assessment of long-term pharmacokinetics of antibody forms. Proof-of-principle was established22 and a patent described23 in 1993 that 124I-labelled antibodies could be quantitatively imaged in vivo in human beings; however, only recently have technical advances in the production of long-lived positron emitters such as 124I allowed the production of sufficient quantities of the radionuclide for use in clinical trials to test the concept of immunotyping by imaging.24 Although 124I is still expensive to procure, the costs are expected to decrease with increased use. Costs of 124I-labelled antibody will be comparable to the Indium-111-labelled antibody currently available for single-photon imaging of prostate cancer. The dosimetry of 124I is comparable to that of 131I, and the US Food and Drug Administration has allowed us to use up to 185 MBq 124I in clinical trials.
We aimed to do a prospective clinical trial to assess whether PET with the use of 124I-cG250 is sensitive and specific enough to identify clear-cell renal carcinoma. To the best of our knowledge, this report represents the first study of positron-emitting forms of radiolabelled G250 in human beings with renal carcinoma.
Section snippets
Patients and procedures
This pilot study was done under an Investigational New Drug application (BB-IND-8851) submitted to the Food and Drug Administration by the Ludwig Institute for Cancer Research. The protocol was approved at Memorial Sloan-Kettering Cancer Center (the sole study site) by the institutional review board, which was responsible for ethics approval. All patients gave written informed consent according to institutional and federal guidelines for inclusion in the study.
All patients were accrued by one
Results
The table shows the characteristics of the patients. All preparations of 124I-cG250 had a radiochemical purity of over 95%. All patients tolerated the 124I-cG250 antibody infusion; there were no allergic or other adverse events related to the study agent, nor were there any agent-related toxic effects. One patient received immunologically inactive 124I-cG250 (patient 4; defined as immunoreactivity under 25%), and was excluded from analysis. 124I-cG250 immunoreactivity (as defined by percent of
Discussion
The results obtained in this prospective PET-imaging trial with 124I-cG250 support the hypothesis that clear-cell renal carcinoma can be distinguished accurately from other renal masses by use of 124I-cG250 antibody PET. The 94% sensitivity and 100% specificity support the potential clinical use of 124I-cG250 antibody PET in renal masses as an alternative to biopsy for characterising lesions; 124I-cG250 PET should be considered in the work-up of incidentally discovered renal masses. These
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