M1a prostate cancer: Results of a Dutch multidisciplinary consensus meeting

Abstract Objectives To determine the consensus of a Dutch multidisciplinary expert panel on the diagnostic evaluation and treatment of de novo and recurrent metastatic prostate cancer (PCa) limited to non‐regional lymph nodes (M1a) in daily clinical practice. Materials and methods The panel consisted of 37 Dutch specialists from disciplines involved in the management of M1a PCa (urology, medical and radiation oncology, radiology, and nuclear medicine). We used a modified Delphi method consisting of two voting rounds and a consensus meeting (video conference). Consensus (good agreement) was defined as the situation in which ≥ 75% of the panelists chose the same option. Results Consensus existed for 57% of the items. The panel agreed that prostate‐specific membrane antigen positron emission tomography/computed tomography (PSMA‐PET/CT) is the most appropriate standard imaging modality to identify de novo (100%) and recurrent (97%) M1a PCa. Androgen deprivation therapy (ADT) combined with radiotherapy to the prostate ± the M1a lesion(s) was most frequently considered an option for de novo M1a PCa. For M1a as recurrent disease, ADT alone, deferring treatment, or local radiotherapy to the M1a lesion(s) were judged to be the most important treatment options. However, no specific indications for treatment choice in relation to disease characteristics could be formulated. Conclusions The Dutch consensus panel preferred PSMA‐PET/CT as the standard diagnostic modality to detect M1a PCa. Although potential treatment options were identified, explicit recommendations could not be formulated. This might (partly) be explained by the absence of high‐level clinical evidence in this subset of patients. Further research is, therefore, strongly encouraged.


| INTRODUC TI ON
According to the TNM classification, M1a prostate cancer (PCa) is defined as the presence of non-regional lymph nodes (LNs), that is, LNs above the bifurcation of the common iliac arteries, while other metastases (bone/visceral) are absent. 1 The detection of M1a disease is highly dependent on the imaging modality used. 2 Modern imaging modalities, such as positron emission tomography/computed tomography (PET/CT) and whole-body magnetic resonance imaging (wbMRI), allow earlier and more precise identification of metastases. 2 Between 2010 and 2018, the age-adjusted incidence of de novo M1a PCa in The Netherlands increased from 0.47 to 1.89 cases per 100,000 population (imaging modality unspecified), and this rise may partly be explained by the use of newer, more sensitive imaging modalities during the more recent years. 3 The median overall survival of this group of patients was 57 months. 3 Patients with metastases limited to the non-regional LNs have better overall survival outcomes than patients with visceral and/or bone metastases. 4 However, evidence on treatment of M1a PCa is limited. Available prospective data on the management of de novo low-volume metastatic disease include patients with limited (less than four) bone metastases and are, therefore, not limited to M1a disease. In addition, the diagnosis of metastatic disease was based on conventional imaging (CT and bone scan). [5][6][7][8][9][10][11][12][13] Also in the recurrent setting, data on management of M1a disease are sparse and mostly retrospective. Few prospective studies investigated the management of oligorecurrent disease, but these were not limited to M1a disease. 14,15 Studies have shown that using newer and more sensitive imaging modalities may lead to a management change of metastatic PCa, however, the impact on oncological outcomes is unknown. 16,17 Altogether, the management of M1a PCa in daily clinical practice is surrounded by many uncertainties. 18 Therefore, we organized a multidisciplinary consensus meeting to determine the state-of-the-art on M1a disease and its clinical implications for The Netherlands.

| Set-up
The consensus meeting was set up by a multidisciplinary Scientific

| Panel composition
The panel consisted of representatives from all disciplines involved in the management of M1a PCa: urology (N = 10), medical oncology (N = 7), radiation oncology (N = 7), radiology (N = 4), and nuclear medicine (N = 9). Selection of panelists was based on clinical and scientific expertise in the field of PCa, geographic spread, and availability to participate in all parts of the study.

| Explorative survey
The first step consisted of an explorative survey on multiple statements and questions related to the definition and management of M1a PCa. The compilation of this survey was based on the clinical expertise of the Scientific Committee members and an explorative literature search for English-language original and review articles published up to April 2020 using the National library of Medicine's PubMed database (H.B.). The search strategy included the following terms: "M1a prostate cancer," "newly-diagnosed M1a prostate cancer," "de novo M1a prostate cancer," "recurrent M1a prostate cancer," "newly-diagnosed low-volume prostate cancer," "de novo low-volume prostate cancer," "oligometastatic prostate cancer," "oligorecurrent prostate cancer," ("non-regional lymph node" OR "distant lymph node" OR "extra-pelvic lymph node" OR "extra-pelvic disease" OR "nodal recurrence") AND "prostate cancer." The abstracts of the retrieved records were screened to identify the most relevant articles. Relevant studies mentioned in the reference list of the identified articles were also taken into account. Additionally, meeting abstracts (2019-2020) reporting on patients with de novo or recurrent M1a disease were included.

| Consensus process
Panelists were asked to complete the explorative survey and provide suggestions for improvement. These survey results were shared with the panelists after which a video conference took place (June 19,2020  The complete survey is shown in the supporting information S1.

| Statistical analysis
Strong agreement (consensus) and fair agreement were defined as the situation in which ≥ 75% or 50%-74% of the panelists, respectively, chose the same option. If the option "can't judge" was chosen, the answer was excluded from the agreement calculations.

| RE SULTS
Consensus existed on 57% of the items (supporting information S2).

| Definition
The TNM classification takes the iliac bifurcation as the anatomical inferior limit for M1a 1 and 39% of the panelists considered this also to be the most relevant level for therapeutic decision making.
A similar share chose for "what is in line with the LN dissection template or irradiation field," and a minority (22%) for the aorta bifurcation. Opinions on whether inguinal and pararectal LNs can be considered as M1a disease were highly dispersed (Table 1).
indicate PCa metastasis (Table 1). Most panelists (89%) considered the combination of size, morphology, and location highly relevant when using conventional CT, while 11% found the combination of size and location to be sufficient for judging LNs. For PSMA-PET/ CT, the most relevant parameters, in addition to a higher uptake, were localization (83%), anatomical substrate on CT (78%), and size of the lesion (50%). For the recurrent setting, almost all panelists (97%) considered PSA > 0.2 ng/mL the most important indication for imaging following radical prostatectomy (RP). For biochemical recurrence after radiotherapy, there was fair agreement (74%) that three consecutive PSA rises, independent of PSA level, are most relevant in this respect ( Figure 2).

| Definition
Although the TNM classification defines M1a as LNs outside the true pelvis ("essentially above the bifurcation of the common iliac arteries"), 1 panelists disagreed on the most relevant anatomical level for therapeutic decisions in patients with non-regional LNs. Dispersed opinions were also seen for considering inguinal or pararectal LNs as non-regional node (M1a)

| Treatment of M1a PCa
Opinions on treatment options for de novo M1a PCa (imaging modal- low-volume disease defined by CT and bone scan. 24 In addition, 92% of these panelists considered it important to distinguish LN-only disease (including non-regional LN metastases) from disease that includes metastatic lesions at other sites. 24 ADT plus radiotherapy to the prostate was most commonly chosen by our panel. This approach is recommended by the EAU guidelines for patients whose first presentation is low-volume metastatic disease as defined by the CHAARTED criteria. 18 An exploratory analysis of the STAMPEDE "M1|RT comparison" (arm H) found that the addition of prostate radiotherapy to standard of care may improve survival among men with only non-regional LNs (M1a) or less than four bone metastases (± LNs, and no visceral metastases) regardless of location. 26 It should be noted that the results of the STAMPEDE trial on radiotherapy to the primary cannot be extrapolated to RP. Currently there are no randomized phase III data available on the use of RP in this setting. with or without ADT and showed a biochemical control rate of 48% at a median follow-up of 16 months. 28 In addition, these patients had a high progression rate (43%) outside the irradiated field. Likewise, in a small prospective single-center study, more than two-thirds of patients with oligorecurrent PCa, limited to the LNs in 65% of patients, developed recurrent cancer outside the area treated with SBRT after 15 months. 29 A retrospective study showed that about one-third of patients with biochemically recurrent disease following RP had PSMA-avid disease that would be missed by standard nodal radiation fields. 30 A recent systematic review showed large heterogeneities in radiotherapy regimens used for nodal oligorecurrent PCa (SBRT vs elective nodal radiotherapy) and the optimal strategy in this setting remains to be determined. 31 Additionally, a recent retrospective study revealed that PET/CT underestimated the burden of nodal prostate recurrence. 32 In the prospective phase II ORIOLE trial, improved progression-free survival was seen for patients with recurrent hormone-sensitive PCa and one to three metastases by conventional imaging who underwent MDT (stereotactic ablative radiotherapy) vs observation. 14  short interval to biochemical failure (after radiotherapy). 33 Also a high Gleason score was associated with worse survival outcomes. 33 The EAU guidelines recommend integrating these factors to stratify patients with biochemical recurrence into low-and high-risk categories. 18   Oprea-Lager, Henk van der Poel, and Derya Yakar Henk van der Poel https://orcid.org/0000-0002-8772-1120