PET/CT imaging of clear cell renal cell carcinoma with ¹²⁴I labeled chimeric antibody

Abstract

Clear cell renal cell carcinoma (ccRCC) presents problems for urologists in diagnosis, treatment selection, intraoperative surgical margin analysis, and long term monitoring. In this paper we describe the development of a radiolabeled antibody specific to ccRCC (124I-cG250) and its potential to help urologists manage each of these problems. We believe 124I-cG250, in conjunction with perioperative Positron emission tomography/computed tomography imaging and intraoperative handheld gamma probe use, has the potential to diagnose ccRCC, aid in determining a proper course of treatment (operative or otherwise), confirm complete resection of malignant tissue in real time, and monitor patients post-operatively.

In the 1980s, researchers characterized G250, a monoclonal antibody (MAb) that binds to carbonic anhydrase IX, a transmembrane protein that is activated in hypoxic conditions to sustain tumor progression. Since that time, G250 has been shown to localize in primary (98%) and metastatic (88%) clear cell renal cell carcinoma (ccRCC) lesions found on human histologic slides under light microscopy [Oosterwijk et al. 1986a; b]. Although MAb G250 occasionally stains positive in several other tumors, it was shown to be a very strong biomarker for ccRCC due to its absence in normal kidney tissue. Thus, the potential use of this MAb for radioimmunoscintigraphy was immediately recognized [Oosterwijk et al. 1986a; b]. However, we are only now seeing that dream coming to fruition.

It was not until 1997, that a chimeric form of G250 (cG250) was developed to reduce human anti-mouse antibody responses (HAMA), and it took an additional 10 years to achieve successful radiolabeling with a suitable radionuclide [Divgi et al. 2007; Steffens et al. 1997]. For example, cG250 labeled with Iodine-131 localized just 30% of metastatic ccRCC lesions using radioimmunoscintigraphy [Brouwers et al. 2002]. Today, however, human clinical trials using Iodine-124 as a radiolabel have demonstrated excellent sensitivity, specificity, positive predictive values, and negative predictive values (94, 100, 100, and 90%, respectively) [Divgi et al. 2007]. As such, positron emission tomography/computed tomography (PET/CT) imaging of ccRCC with ¹²⁴I-cG250 may change the workup of a patient with an incidental kidney mass, the treatment of ccRCC, and the way patients with a history of ccRCC are monitored.

As diagnostic imaging advanced, the presentation of ccRCC changed from a large palpable symptomatic mass, to an ‘incidentaloma’ found on CT. Given that up to 30% of these lesions, when less than 4 cm in size, are benign, urologists are faced with a dilemma: perform a nephrectomy on a potentially benign mass, or watch a potentially aggressive tumor progress. It would be an advantage to be able to obtain a histologic diagnosis based on preoperative imaging to avoid invasive biopsies and, worse yet, unnecessary surgeries.

PET/CT imaging with ¹²⁴I-cG250 may eliminate this predicament, as it is both highly sensitive and specific for ccRCC. Thus, those ‘incidentalomas’ that are, in fact, ccRCC appear on PET/CT imaging (Figure 1). If there is a signal on PET imaging, the patient likely has ccRCC.

Figure 1.

Preoperative CT (a), PET (b), and fused PET/CT (c) images obtained 4 days post-injection of 5.2 mCi (192.4 MBq) 124-I cG250 show a well-defined tumor mass in the left kidney.

The utilization of PET/CT imaging with chimeric MAbs has been given the name: ‘imaging histology’ amongst our imaging and radio-guided surgery group, and describes the non-invasive, in vivo, three-dimensional ‘mapping’ of pathology on a histologic level. However, the potential utility of PET/CT imaging of ccRCC with ¹²⁴I-cG250 extends beyond mere diagnosis. Imaging histology allows a surgeon to more precisely plan their approach and, perhaps, predict and plan surgical margins before the patient even enters the operating suite [Hall et al. 2008]. Once in the operating suite, a hand-held gamma probe may be used in real-time to verify that all of the radioactivity, and thus, the tumor, has been excised. This intraoperative information may then be further verified by immediately acquiring an ex vivo PET/CT scan of the whole specimen and/or repeating the PET/CT scan of the patient after surgery (Figure 2) [Povoski et al. 2009; Cohn et al. 2008, Hall et al. 2008, Povoski et al. 2008; Hall et al. 2007; Sarikaya et al. 2007]. The combined use of perioperative ¹²⁴I-cG250 PET/CT imaging and the intraoperative handheld gamma probe may provide more accurate information than does frozen section with the additional advantage of providing real-time information to the urologist.

Figure 2.

Digital photographs of a whole (a) and bisected (b) ex vivo left kidney specimen show extent of ccRCC. A fused PET/CT image (c) of the kidney obtained prior to bisection of the tissue indicates a region of intense tracer uptake that correlates well with the gross tumor location.

After a diagnosis of a solid renal neoplasm is made, urologists face a dilemma whether to perform a partial or total nephrectomy. Recent evidence has shown that partial nephrectomy has similar oncologic outcomes with the added advantage of sparing useful nephrons [Fergany et al. 2006; 2000]. Yet a study based on NCI data from 1995–2002 showed that only 18% of patients with tumors measuring 4 cm or smaller were treated with partial nephrectomy [Huang et al. 2009]. The percentage of patients treated with partial nephrectomy increased each year (up to 26% in 2002), but the treatment is slow to become the standard of care. Whether this is due to a lack of training, relative comfort with traditional radical excision, concern over leaving tumor behind, or any number of other factors is unclear. Whatever the reason, we believe that perioperative PET/CT utilizing ¹²⁴I-cG250 could influence more widespread acceptance of partial nephrectomy with its advantages of preoperative planning and ex vivo margin analysis.

Additionally, the utility of ¹²⁴I-cG250 PET/CT imaging for verification of complete tumor resection could extend to other treatment modalities such as radiofrequency ablation (RFA) and cryotherapy (cryo). Since neither RFA nor cryo involve resection of malignant tissue, the urologist would have to allow for the radioactive iodine molecules to completely decay, a delay of approximately 40 days from the time of injection, before assessment of the procedure is possible. As a result, real-time RFA and cryo treatment assessment will be unavailable, but a follow-up PET/CT image utilizing ¹²⁴I-cG250 may assess the effectiveness of these therapies; no signal, no ccRCC.

Finally, ¹²⁴I-cG250 imaging histology may be a powerful tool for the evaluation of recurrent and metastatic disease. Current PET/CT imaging to evaluate ccRCC patients for both recurrent and/or distant metastatic disease is problematic, largely due to the non-specific nature of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) as a radiotracer. The theory behind ¹⁸F-FDG PET imaging is that tumors will utilize a higher concentration of radiolabeled glucose than will normal cells. However, cells (both tumor and normal cells) uptake glucose at varying rates, and the difference between glucose concentration in normal cells as compared with tumor cells is not always large enough to be appreciated by PET/CT imaging. While ¹⁸F-FDG has shown promising results in several other tumor types, the excretion of ¹⁸F-FDG via the urinary system, its low sensitivity, and high rates of both false positivity and false negativity in primary and metastatic RCC patients limits its use for urologists [Kang et al. 2004; Majhail et al. 2003; Miyakita et al. 2002]. The high sensitivity and positive predictive value of ¹²⁴I-cG250 PET/CT would make it a very effective alternative to ¹⁸F-FDG PET/CT for monitoring ccRCC patients for metastasis and recurrence.

It is important to realize that ¹²⁴I-cG250 is specific only to ccRCC, and therefore provides no further useful information concerning other tumor types. This limits the utility of ¹²⁴I-cG250 PET/CT as a potential diagnostic evaluation for all renal masses. However, it is still a strong biomarker for the most frequent renal tumor type. Moreover, the data and methodologies presented here illustrate the potential for using a specific, radiolabeled MAb for detection, diagnosis, confirmation of resection, and postoperative surveillance for cRCC. However, this paradigm could be extended to a wide range of cancer types with the development of cancer specific antibodies linked with radionuclides.

At this time, modern imaging modalities have proved inadequate for the detection and monitoring of ccRCC patients. Specifically, PET/CT imaging with ¹⁸F-FDG has been shown to have poor sensitivity and specificity in the urinary system. However, new imaging methodologies utilizing radiolabeled chimeric antibodies, such as ¹²⁴I-cG250 for ccRCC, can potentially extend far beyond the traditional diagnostic role of PET/CT imaging. The urologist may now have a reliable tool to identify patients with ccRCC. Images will aid the determination of tumor margins preoperatively, in the decision to perform a partial or total nephrectomy, and help ensure clear surgical margins intraoperatively with the utilization of a handheld gamma probe. It can also provide an accurate method for monitoring all three non-pharmacologic therapies (surgery, cryoablation, and radiofrequency ablation) for ccRCC. Long term data are not available at this time, but there is promise that PET/CT imaging with chimeric antibodies may lead to improved patient outcomes.

Conflicts of interest statement

None declared.