A population-based study of the clinical utility of ¹⁸F–choline PET/CT for primary metastasis staging of high-risk prostate cancer

The European Association of Urology (EAU) guidelines recommend conventional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) together with ^99mTc bone scintigraphy (BS) – either as planar BS or single-photon emission computed tomography (SPECT) – as the current standard primary imaging for metastasis for men with high-risk prostate cancer (Mottet et al., 2017). For men with convincing findings of distant metastasis on imaging, curative treatment is usually considered inappropriate. Positron emission tomography fused with computed tomography (PET/CT) with ¹¹C- or ¹⁸F–marked choline as tracer has for more than a decade been evaluated for detecting bone and lymph node metastases in men with prostate cancer in a variety of settings (Wondergem et al., 2013; Ceci et al., 2015; Eyben & Kairemo, 2014; Mapelli & Picchio, 2015; Langsteger et al., 2011; Evangelista et al., 2016). The specificity of ¹¹C- and ¹⁸F–choline PET/CT has generally been reported as high, around 90–95%, in primary lymph node staging (Evangelista et al., 2013). The sensitivity is lower, around 50%, but this is still higher than for CT, MRI and BS (Evangelista et al., 2016; Even-Sapir et al., 2006; Pinaquy et al., 2015; Evangelista et al., 2015; Heck et al., 2014).

We previously reported on the performance of ¹⁸F–choline PET/CT in 90 men with high-risk prostate cancer, defined as prostate specific antigen (PSA) ≥ 20 ng/mL and/or Gleason score (GS) 8–10, and a normal or inconclusive planar BS (Kjölhede et al., 2012). PET/CT detected widespread metastasis in 20%, which led to a change from curative to non-curative treatment, and less widespread metastasis in a further 19% of the men. However, the studied men were probably a selected group with more adverse prognostic factors and a higher than average risk of metastases, so the clinical value of choline PET/CT for the entire group of men with high-risk prostate cancer might have been overestimated.

Moreover, PET/CT is an expensive imaging modality and access to the machines is limited, so using it for all patients with high-risk prostate cancer would be costly and may put a difficult pressure on PET/CT resources. Known independent risk factors predicting metastatic disease are e.g. high PSA levels, high GS, locally advanced disease and proportion of positive biopsy cores (Risko et al., 2014; Porcaro et al., 2017). The Briganti nomogram weighs these factors for a score predicting the probability of finding lymph node metastasis with an extended pelvic lymph node dissection, and this nomogram has also been externally validated (Briganti et al., 2012; Hansen et al., 2013). These risk factors, or the Briganti nomogram, could possibly be used to define a subgroup of men where choline PET/CT has the greatest clinical utility and cost-effectiveness.

The aim of this study was to assess the overall clinical utility of ¹⁸F–choline PET/CT for primary metastasis staging of high-risk prostate cancer, in terms of detection rate of suspected metastasis. We also aimed at, if possible, identifying a subgroup of men with a low likelihood of positive scans, for which metastasis staging might be omitted.

A total of 410 men were registered in the NPCR as diagnosed with high-risk prostate cancer in the two counties from 1 May 2013 to 31 Dec 2014. Exclusions and all imaging performed are detailed in Fig. 1.

Of the 213 men who had a choline PET/CT, 43 (20%) had positive findings, 51 (24%) had an inconclusive scan, and 119 (56%) had no abnormal findings. Of the 43 men with positive findings, 12 (28%) had positive skeletal sites (stage cM1b/c), 14 (33%) had positive retroperitoneal lymph nodes above the aortic bifurcation (stage cM1a), while 17 (40%) had positive pelvic lymph nodes only (stage cN1), with either pathologically enlarged or distinct choline uptake (or both). All lymph nodes that were pathologically enlarged lymph nodes also had distinct choline uptake. Two of the men with positive skeletal sites had no positive lymph nodes. Of the 162 men who performed both a PET/CT and a BS, seven had positive skeletal findings on the BS which were all detected by choline PET/CT. Of the 144 men who performed a BS before the PET/CT, 139 had normal or inconclusive findings on BS. Of these, 31 men (22%) had positive PET/CT findings. The management was changed from curative to non-curative for 40 of the 213 men (19%) due to the PET/CT findings. All 40 men who received non-curative treatment had hormonal therapy. Two of them also had docetaxel and eight received palliative prostate radiation therapy.

Logistic regression analysis of possible predictive factors of positive findings on choline PET/CT are shown in Table 2, with the Briganti nomogram showing best discrimination with an AUC of 0.82 (Fig. 2). Figure 3 shows the results of the PET/CT scans grouped by their risk of metastasis. The ratio of inconclusive to negative scans was not significantly different between the risk groups (p = 0.87).

	Univariate			Multivariate model 1		Multivariate model 2
				AUC = .76 (.68–.83)		AUC = .77 (.70–.85)
	OR (95% CI)	p	AUC	OR (95% CI)	p	OR (95% CI)	p
PSA < vs ≥ 20 ng/ml	2.0 (1.0–4.0)	.05	.59 (.50–.69)	1.6 (0.8–3.5)	.198
GS < vs ≥ 8	1.9 (0.8–4.1)	.13
T < vs ≥ 3	2.7 (1.4–5.3)	.005	.61 (.51–.71)	1.8 (0.8–3.7)	.141
Proportion positive biopsy cores	1.4 (1.2–1.7)	<.001	.75 (.67–.83)	1.4 (1.2–1.6)	<.001	1.4 (1.1–1.6)	<.001
No. high-risk criteria			.68 (.58–.77)
1 (ref)	1					1
2	2.3 (1.0–5.0)	.043				1.7 (0.8–4.0)	.199
3	8.1 (3.1–21)	<.001				3.9 (1.4–11)	.010
Probability of N1a	1.5 (1.3–1.8)	<.001	.82 (.75–.88)

OR odds ratio, CI confidence interval, PSA prostate specific antigen, T clinical local tumor stage, AUC area-under-the-curve

^aProbability of lymph node metastases according to the Briganti nomogram (Briganti et al., 2012)

Almost all men with positive choline PET/CT findings (98%) had ≥20% risk of lymph node metastasis according to the Briganti nomogram. In this ≥20% risk group, which constituted 65% of the 213 men who performed a PET/CT scan, 30% had positive PET/CT findings. Among the remaining 35% of the men, with <20% risk of lymph node metastasis, only 1% had positive PET/CT findings. In the whole group of 317 men planned for curative treatment (except for the three diagnosed with TUR-P), 45% had <20% risk of lymph node metastasis. The number of high-risk criteria did not discriminate between men with positive versus negative PET/CT scans as accurately as the Briganti nomogram; as many as 12% of the 119 men with only one high-risk criterion had positive scans.

In this population-based study of men with high-risk prostate cancer initially considered for curative treatment, 20% had positive ¹⁸F–choline PET/CT findings, which could potentially change their clinical management. The probability of lymph node metastasis according to the Briganti nomogram with a cut-off of 20% discriminated between men with a high (30%) and men with a low (1%) chance of a positive PET/CT scan.

Previous studies on primary prostate cancer staging with choline PET/CT have reported quite variable detection rates for lymph node metastases on choline PET/CT, likely because of differences in prognostic factors among included patients. A systematic review and meta-analysis showed an overall rate of positive choline PET/CT findings of 16% in a total of 661 men, which is well in accordance with the present results (Eyben & Kairemo, 2014). Evangelista and co-workers in a recent review found detection rates of lymph node metastases varying between 11 and 93% (Evangelista et al., 2016). These results underscore the need for selecting the right patients for PET/CT scans.

Like in the present study, Schiavina et al. also evaluated, amongst others, the Briganti nomogram in relation to ¹¹C–choline PET/CT for predicting lymph node metastasis in 57 men and found no statistically significant differences in the AUC between choline PET/CT and the Briganti nomogram (Schiavina et al., 2008), but they made no attempt to define which patients most or least benefited from the scans. Briganti and co-workers investigated the clinical utility of BS in a large cohort of men with newly diagnosed prostate cancer (Briganti et al., 2010). Their results suggested that all patients with GS 8–10 and those with both the two other risk criteria should perform a BS. In our study, positive choline PET/CT findings were less common (12%) among men with one high-risk criterion only, so routine use of choline PET/CT in this subgroup of men with high-risk disease may not be cost-effective. However, the Briganti nomogram performed better than simple counting of high-risk criteria at discriminating between men with a low from men with a high risk of positive choline PET/CT findings. It is possible that some of the inconclusive scans in the present study represented metastatic disease, but as the proportion of inconclusive scans was similar regardless of the clinical risk of metastasis it is unlikely that a high proportion of these inconclusive findings represented metastases. Inflammatory response in lymph nodes may be responsible for some positive and inconclusive findings (Schwarz et al., 2016). The proportion of inconclusive scans is higher in the current than in previous studies. The reasons for this are unclear, but could possibly be related to the definitions of positive scans which vary from study to study.

Few of the studied patients with extra-iliac metastasis on PET/CT received treatment with curative intent, but there is an increasing interest in multimodal treatment of men with limited metastatic burden (Bayne et al., 2016). Surgical removal of lymph node metastases and stereotactic radiation to oligo-metastatic spread to lymph nodes and bone in men with biochemical recurrence after radical local treatment have been associated with favorable outcomes in institutional series (Osmonov et al., 2016; Suardi et al., 2015; Pasqualetti et al., 2016), and there is at least one ongoing randomized controlled trial of metastasis-directed treatment of oligo-metastasis following recurrence after previous local therapy (Decaestecker et al., 2014). The favorable outcome after treatment of oligo-metastatic recurrence suggests that combined local and metastasis-directed therapies might be of benefit for men with primary oligo-metastatic disease, but results from randomized trials are needed to prove a survival benefit.

The strengths of our study include its population-based design and that most of the men with high-risk disease had a choline PET/CT. The limitations are primarily related to the retrospective design and that the PET/CT scans were not reevaluated in a blinded fashion. Moreover, there seems to have been some selection of men with more adverse prognostic factors for PET/CT scanning (Table 1). Finally, PET/CT could not be compared with the combination of CT and BS, which is the recommended metastasis staging in the EAU guidelines. The sensitivity of CT for detecting lymph node metastasis is, however, low and there is clearly a need for more sensitive imaging (Mottet et al., 2017). Other PET/CT tracers, such as ¹¹C–acetate and various PSMA ligands, are available, but they have not been evaluated as extensively as choline, especially not regarding their clinical utility (Perera et al., 2016; Strandberg et al., 2016; von Eyben et al., 2016; Michaud & Touijer, 2017).

In this population-based study, ¹⁸F–choline PET/CT for primary staging of high-risk prostate cancer detected suspected metastases in one fifth of the patients. The probability of positive findings on ¹⁸F–choline PET/CT was, however, low (1%) when the probability of lymph node metastasis according to the Briganti nomogram was less than 20%, suggesting that imaging (including the less sensitive modalities CT, MRI and BS) is not necessary in this subgroup of men with high-risk prostate cancer.