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  Table of Contents 
TECHNICAL UPDATE
Year : 2015  |  Volume : 31  |  Issue : 1  |  Page : 22-27
 

Management of urological malignancies: Has positron emission tomography/computed tomography made a difference?


Department of Urology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication1-Jan-2015

Correspondence Address:
Dr. Thampi John Nirmal
Department of Urology, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-1591.145296

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   Abstract 

Positron emission tomography/computed tomography (PET/CT) technology has been a significant, but expensive addition to the oncologist's armamentarium. The aim of this review was to determine the clinical utility of PET/CT in urological oncology, its impact on disease outcome and cost-effectiveness. We searched MedLine and peer reviewed journals for all relevant literature available online from the year 2000 until January 2014 regarding the use of PET/CT in the management of urological malignancies. 11 C-choline PET/CT has emerged as a powerful tool for assessment of biochemical relapse in prostate cancer. Use of novel radiotracers like 124 I-girentuximab has shown promise in the diagnosis of clear cell renal carcinoma. Fluorodeoxyglucose PET has a proven role in seminoma for the evaluation of postchemotherapy residual masses and has shown encouraging results when used for detection of metastasis in renal, bladder, and penile cancer. Introduction of novel radiotracers and advanced technology has led to a wider application of PET/CT in urological oncology. However, testicular seminoma aside, its impact on disease outcome and cost-effectiveness still needs to be established.


Keywords: Bladder cancer, penile cancer, positron emission tomography/computed tomography, prostate cancer, renal cell carcinoma, testicular germ cell tumor, urological


How to cite this article:
Nirmal TJ, Kekre NS. Management of urological malignancies: Has positron emission tomography/computed tomography made a difference?. Indian J Urol 2015;31:22-7

How to cite this URL:
Nirmal TJ, Kekre NS. Management of urological malignancies: Has positron emission tomography/computed tomography made a difference?. Indian J Urol [serial online] 2015 [cited 2019 Jun 19];31:22-7. Available from: http://www.indianjurol.com/text.asp?2015/31/1/22/145296



   Introduction Top


The hybrid positron emission tomography/computed tomography (PET/CT) technology was first introduced by Townsend, Nutt, and Beyer in 1998 [1] and has since, become an important addition to the oncologist's armamentarium. The integration of anatomic imaging along with functional characterization allows for improved diagnosis, staging, assessment of treatment response, and early detection of disease relapse/recurrence. However, the full potential of PET/CT is yet to be realized in urology due to several limitations. We searched MedLine and peer reviewed journals for all relevant literature available online from the year 2000 until Jan 2014 regarding the use of PET/CT in the management of urological malignancies. This review aims to critically appraise the clinical utility of PET/CT in the management of urological malignancies, its impact on disease outcome and also address its cost-effectiveness.


   Radiotracers and Instrumentation Top


Radionuclides used in PET scanning are generally isotopes with short half-lives such as carbon-11 (20 min), nitrogen-13 (10 min), oxygen-15 (2 min), and fluorine-18 (110 min). Radiotracers can be divided into two groups: Metabolic tracers (incorporated into compounds normally used by the body such as glucose) and receptor-specific radiopharmaceuticals. [2]

The most widely used radiotracer in oncology is fluorodeoxyglucose (2-fluoro-2-deoxy-d-glucose, FDG), a glucose analogue. Unfortunately, 18 F-FDG is not an ideal radiotracer for use in urology due to its urinary elimination, which prevents the proper visualization of the bladder and its surroundings. [2]

Since 1998, significant advances have been made in both PET and CT technology. Availability of fast scintillators with high stopping power such as: Lutetium orthosilicate and gadolinium orthosilicate have made time-of-flight PET possible. This has led to improvement in not only lesion detection but also spatial resolution. [3] Moreover, incorporation of a 64-slice CT enables the acquisition of high quality whole body images in a matter of seconds.


   Rostate Cancer Top


Imaging in prostate cancer would have clinical utility only if it is able to (1) preoperatively identify extra-prostatic extension, seminal vesicle invasion and thereby impact the decision to do a nerve preserving radical surgery, (2) identify metastatic lymph nodes preoperatively and prevent a surgery, and (3) accurately detect relapse/recurrence following prior therapy.

Majority of the prostate cancers are not 18 F-FDG avid owing to their poor metabolic activity. Moreover, increased urinary elimination of FDG tends to obscure pelvic pathology. Hence, 11 C- or 18 F-choline have replaced FDG in the evaluation of prostate cancer and have shown promising results. [4]

Local staging

11 C-choline PET/CT had a sensitivity of 55-87%, specificity of 43-87%, and an accuracy of 60-84% when used for the detection of primary malignancy. [5],[6],[7],[8]

Martorana et al. showed that the sensitivity improved to 83% when the lesions were > 5 mm compared with only 4% for smaller lesions. [7] The low specificity rates are attributed to confounding uptake of the tracer in the presence of benign prostatic hypertrophy, prostatitis, high-grade prostatic intraepithelial neoplasia, urinary activity in the base of the bladder or urethra, and by normal tissues surrounding the prostate gland, for example, pelvic musculature and rectum. [9] Moreover, clinically significant correlation could not be established between 11 C-choline uptake by localized prostate cancer and serum prostate specific antigen (PSA) levels, Gleason score, and tumor grade. [8],[10]

On comparing 11 C-choline PET/CT with other imaging modalities for local staging, T2-weighted magnetic resonance imaging (MRI) imaging combined with a dynamic contrast enhanced imaging showed superior sensitivity and specificity. [11] Even for evaluation of suspected local recurrence following radical prostatectomy (RP), Panebianco et al. documented that endorectal coil dynamic contrast-enhanced MRI/MR spectroscopy was superior to 18 F-choline PET/CT. [12]

Detection of lymph node metastasis

The sensitivity and specificity for detecting lymph nodes by 11 C-choline PET/CT in untreated cases later confirmed by histopathology were 60-78% and 82-98% respectively. As expected, the detection rates improved with increase in the size of the metastatic nodes with 0% detection rate for nodes <2 mm in size, 25-30% for 2-4.9 mm nodes, 33-43% for 5-9.9 mm nodes, and 77-90% for nodes measuring 10 mm and larger. [13],[14] Budiharto et al. [15] showed that in patients at high clinical risk for lymph node metastasis who were CT negative, the sensitivity of detecting lymph node metastasis was only 19% with specificity of 95%.

When used to detect recurrence of disease in pelvic and retroperitoneal lymph nodes following RP, Scattoni et al. could achieve a sensitivity, specificity, and accuracy of 66%, 100%, and 92%, respectively. [16] A meta-analysis looking at CT and MRI detection rates of lymph node metastasis revealed pooled sensitivity and specificity rates of 39% and 82%, respectively. [17]

Though 18 F-choline PET/CT seems to perform better than conventional imaging, its accuracy is not sufficient to replace pelvic lymph node dissection as the gold standard for initial staging. [18] Hence, PET/CT has no role in the initial staging of prostate cancer. However, in the select group of high risk prostate cancer (PSA > 20 ng/mL, Gleason 8-10, locally advanced tumor) 18 F-choline PET/CT could be used to detect metastasis and thereby change management as shown by Beheshti et al. [19] in approximately 20% of their high-risk study group. This would help prevent the cost and morbidity of RP/radiotherapy (RT) in this subgroup.

Detection of skeletal metastasis

Picchio et al. [20] compared 11 C-choline PET/CT and bone scintigraphy for the detection bone metastasis in patients showing PSA progression following primary treatment and found that though the sensitivity (89% vs. 70-100%) of choline PET/CT was poorer, it exhibited a higher specificity (98-100% vs. 75-100%), and accuracy (95-96% vs. 85-93%). Osteoblastic bone lesions occasionally show no choline uptake and need to be picked up on CT. [20] Increased uptake of NaF reflects the rapid bone turnover associated with osteoblastic skeletal metastasis. 18 F-NaF (fluoride) PET/CT when used to detect bone metastasis in patients with high-risk prostate cancer showed sensitivity and specificity of 100%. Beheshti compared 18 F-choline PET and 18 F-fluoride PET and found that though choline PET helped in early detection of bone marrow involvement, fluoride PET was better for sclerotic lesions. [21] In another study, Beheshti et al. [22] showed that the degree of sclerosis had an inverse relation with choline activity. Sclerotic lesions on CT with a Hounsfield unit > 825 showed no choline activity and may represent healed bone lesions in patients who have received androgen deprivation. Despite its high sensitivity and specificity, 18 F-fuoro PET and 18 F-choline PET have not replaced bone scintigraphy and the European Association of Urology (EAU) guidelines recommend their use for staging in equivocal cases only. [23]

Detection of prostate cancer recurrence

11 C-choline PET/CT has been used to assess biochemical relapse after treatment. In a study by Giovacchini et al., [24] the sensitivity, specificity, and accuracy of choline PET for detection of prostate cancer in previously detected prostate cancer was 85%, 93%, and 89%, respectively. They also showed that sensitivity improved with increasing PSA levels and the PSA cutoff with the best sensitivity (73%) and specificity (72%) profile was 1.4 mg/mL. Advanced age, initial pathological stage, and prior biochemical failure were factors which predicted higher detection rates.

Schillaci et al. [25] used 18 F-fluorocholine PET/CT to restage patients post RP and found detection rates of 20% for a PSA < 1 ng/mL, 55% for a PSA of 1-2 ng/mL, 80% for a PSA of 2-4 ng/mL, and 87% for a PSA >4 ng/mL. Ceci et al. [26] has shown that 11 C-choline PET/CT can detect relapse in patients with hormone-resistant prostate cancer and advocated that withdrawal of hormone therapy may not be necessary prior to scanning. Finally, Soyka et al. [27] have shown that 18 F-fluorocholine PET/CT results could change the management of at least 48% of patients with disease recurrence following prior treatment (RP/RT or combination).

Hence, choline PET/CT has emerged as a powerful tool for evaluation of biochemical relapse in the setting where conventional imaging (CT/MRI or bone scan) has failed to pick up disease. Thought the PSA level at the time of scanning is a strong predictor, Picchio et al. [28] advise against the use of choline PET/CT for restaging post RP for PSA levels <1 ng/mL and this has been reiterated by the latest EAU guidelines. [23] This would help cut costs and avoid unnecessary radiation exposure.


   Renal Cancer Top


The detection of renal cell carcinoma (RCC) with PET is often hampered because most radiotracers, for example, FDG are excreted through the kidneys. Diuretics and bladder catheterization have been tried to minimize this limitation.

Diagnosis and staging of renal cell carcinoma

When FDG PET was used for the diagnosis of RCC, the maximum standard uptake values (SUVmax) within the region of interest varied between <1.5 and >24 [29],[30] and no cutoff value could be identified, which would be specific for RCC. No correlation was found between the SUV and the subtype of RCC. [31] Moreover, owing to the urinary activity of FDG, significant tumor size correlation was seen only if the lesion was >5 cm.

However, FDG PET is highly sensitive for metastatic RCC and showed activity in 95% of the metastatic lesions picked up by CT. [32] A meta-analysis investigated the role of 18 F-FDG PET in RCC [33] and concluded that 18 F-FDG PET is useful in the diagnosis and staging of metastatic lesions with a sensitivity of 87% and a specificity of 93%, but presents limitations when diagnosing primary tumors.

In recent times, novel receptor specific radiotracers have been used to overcome the limitations of FDG. The antibody cG250 (girentuximab) acts against carbonic anhydrase 9, which is over-expressed in clear cell carcinomas. In a phase III study, sensitivity and specificity of 124 I-cG250 PET/CT was 86.2% and 85.9% (vs. 75.5% and 46.8% for CT), respectively for identifying clear cell RCC. [34] Hence, girentuximab PET/CT allows for accurate and noninvasive diagnosis of clear cell RCC and thus may help in formulating the best management protocols for these patients.

Assessment of treatment response

Higher SUVmax indices on FDG PET correlated with poorer prognosis and overall survival in patients with RCC. [29],[30] A decrease in SUVmax of <20% following therapy also portends poor prognosis. [35] PET/CT has still not been incorporated into the commonly used criteria for evaluating disease response, for example, the response evaluation criteria in solid tumors (RECIST) and is currently used only as an adjunct. [36]


   Testicular Germ Cell Tumors Top


The prognosis of testicular cancer is excellent with 5 years survival rates >95%. PET-CT must be able to overcome the lacuna in current imaging tools in order to make any significant impact in current management protocols. However, this has been marred by the major limitations of FDG PET/CT, which include inability to detect lesions < 1 cm and also distinguish between mature teratoma from normal/necrotic tissue. [37]

Nonseminomatous germ cell tumor

In the study by National Cancer Research Institute Testis Cancer Clinical Studies group, [38] 18 F-FDG PET/CT failed to detect micrometastasis resulting in unacceptable retroperitoneal relapse in a high risk study group on surveillance. Oechsle et al. [39] concluded that 18 F-FDG PET was unable to provide additional information to which CT scan and serum markers provided and was not sufficiently sensitive to identify patients at low-risk of relapse to guide management decisions.

Seminomatous germ cell tumor

De Santis et al. [40] correlated size of the residual lesions on CT (>3 cm or ≤ 3 cm) with the presence or absence of a viable residual tumor. The diagnostic values of 18 F-FDG PET were as follows: Specificity 100%, sensitivity 80%, positive predictive value 100%, and negative predictive value 96%, respectively. These results were corroborated in another study by Becherer et al. [41] In seminomatous germ cell tumors (GCT), 18 F-FDG must be used for evaluating residual masses >3 cm after chemotherapy, obviating the need for a morbid surgery like retroperitoneal lymph node dissection.


   Bladder Cancer Top


As already emphasized, the role of 18 F-FDG PET for the detection of localized disease is limited due to the urinary excretion of 18 F-FDG. Forced diuresis and dual phase protocols have been employed to improve the sensitivity and specificity of detecting residual/recurrent disease as well as nodal staging.

Local staging or restaging

A recent study using an adaptation of the dual phase protocol enabled excellent urinary tracer washout and achieved a sensitivity, specificity, and accuracy of 92%, 87%, and 89%, respectively. [42] The systematic review by Lu et al. [43] reported pooled estimates of diagnostic accuracy of FDG PET/CT and FDG PET compared with pathological proof (biopsy or surgery) and/or follow-up for staging and/or restaging of patients with bladder carcinoma. Pooled sensitivity was 82% and specificity 89%.

Detection of metastasis

18 F-FDG PET had sensitivity and specificity of 81% and 94% for detecting metastasis and was able to affect a change in management of 68% of the patients. [44] FDG PET also showed better sensitivity and specificity for detecting bone metastasis than did bone scintigraphy. [45]

Penile Cancer

Due to the significant potential morbidity of inguinal and pelvic lymphadenectomy, the search for an imaging modality that can accurately identify lymphatic metastases continues. A systematic review by Sadeghi et al. [46] reports pooled estimates of diagnostic accuracy for FDG PET/CT compared with inguinal lymph node dissection and/or follow-up. Pooled sensitivity of PET/CT is 80.9%, pooled specificity 92.4%. In patients with clinically palpable nodes, the pooled sensitivity improved to 96.4% and hence, may justify the use of PET/CT in this subgroup. However, false negative rates are high and PET/CT is poor in detecting micrometastasis.

Cost Effectiveness of PET/CT

PET/CT is a potentially important but very expensive investigation. High end PET/CT systems cost anywhere between 2.5 and 3 million dollars and operational costs including service costs are substantial. The only one systematic review looking at the economic evaluation on the use of PET/CT for cancer staging had disappointing results. [47] However, the review did not include any of the urological malignancies and the methodology used for analysis was also questionable.

Future Perspectives

Though more expensive than CT, the advantages of MRI include reduced radiation exposure and the ability to measure tissue properties such as diffusion, enhancement and specific metabolites with high resolution. Hence, the hybrid imaging modality of PET/MRI combines the highest anatomical detail as well as biochemical and functional information provided by MRI with the metabolic, molecular, and physiologic information from PET. The first PET/MRI was initiated into clinical use in 2007for imaging the brain and since then technical advancements have paved the way for its use for molecular imaging in oncology. [48] In a preliminary study, 68 Gallium-prostate specific membrane antigen tagged PET/MRI proved superior than PET/CT in detecting local recurrence including lymph node metastasis < 10 mm in cases of biochemical failure following primary treatment of prostate cancer. [49]


   Conclusion Top


PET/CT in urological oncology is challenging because of the urinary excretion of many tracers. The only accepted indication for 18 F-FDG PET/CT is for the evaluation of postchemotherapy residual masses in seminomatous GCT. Novel radiotracers like 124 Girentuximab may be used for the diagnosis of clear cell RCC. 11 C-choline PET/CT has emerged as a powerful tool for assessment of biochemical relapse in prostate cancer. FDG PET/CT has also shown improved sensitivity and specificity for detection of metastatic disease in renal, bladder and penile cancer. Development of new radiotracers together with technological advances and further studies including economic evaluation are needed to further establish the role of PET/CT in the management of urological malignancies.

 
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    Abstract
   Introduction
    Radiotracers and...
   Rostate Cancer
   Renal Cancer
    Testicular Germ ...
   Bladder Cancer
   Conclusion
    References

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