Salvage focal brachytherapy in castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy.

Introduction: Treatment strategy for castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established. Case presentation: We described a case of castration-resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate-specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate-specific antigen progression-free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months.
Conclusion: Salvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration-resistant prostate cancer with neuroendocrine differentiation.

apparent diffusion coefficient

androgen deprivation therapy

androgen receptor

chromogranin A

castration‐resistant prostate cancer

computed tomography

clinical target volume

diffusion‐weighted imaging

external beam radiotherapy

hematoxylin and eosin

immunohistochemical

intensity‐modulated radiation therapy

magnetic resonance imaging

Neuroendocrine Prostate Cancer

non‐small cell lung cancer

neuron‐specific enolase

Prostate Cancer Clinical Trials Working Group 3

prostate‐specific antigen

prostate‐specific membrane antigen

small cell lung cancer

synaptophysin

treatment‐related Neuroendocrine Prostate Cancer

Treatment strategy for castration‐resistant prostate cancer (CRPC) with neuroendocrine differentiation after radiation therapy has not been established. We described a successful case of CRPC with neuroendocrine differentiation (CRPC‐NE) after initial external beam radiotherapy. Salvage focal brachytherapy for CRPC‐NE can be one of the treatment strategies for local recurrence of CRPC.

Introduction

The PCWG3 defines CRPC as a PSA level of >1 ng/mL after ADT. In addition, according to the Phoenix definition, biochemical failure of prostate cancer after EBRT is defined as a PSA rise of ≥2 ng/mL above the lowest level. Since there is no PSA criterion of prostate cancer recurrence after initial EBRT followed by salvage ADT for biochemical recurrence of prostate cancer, the CRPC definition is often used instead. In this report, we described one case of CRPC‐NE that recurred with low serum PSA levels after initial EBRT followed by salvage ADT for biochemical recurrence of prostate cancer, followed by hemi‐gland focal salvage iodine‐125 prostate brachytherapy.

Case presentation

In 2013, a 66‐year‐old man presented with a serum PSA level of 24.6 ng/mL, and prostate cancer was suspected. A transrectal prostate needle biopsy was performed, which gave a Gleason score of 4 + 3. The patient was diagnosed with cT1cN0M0 prostate cancer, and he was administered EBRT of 70 Gy. Initially, he showed a good response to the treatment (lowest serum PSA level = 3.68 ng/mL). However, his serum PSA level gradually increased to 5.9 ng/mL in May 2015, and he was diagnosed with biochemical recurrence of prostate cancer according to the Phoenix definition. Subsequently, he was referred to our hospital for subsequent therapy and administered salvage ADT. Leuprorelin acetate (11.25 mg/3 months or 22.5 mg/6 months) and bicalutamide (80 mg/day) were used. Initially, he showed a good response with decreased serum PSA levels of <0.01 ng/mL for ~3 years. However, in February 2020, his serum PSA level began to increase slightly and reached 0.10 ng/mL (Fig. 1). The serum testosterone level was 17 ng/dL when the serum PSA level increased to 0.06 ng/mL. Despite low serum PSA levels, local recurrence was suspected because of a continuous increase of serum PSA levels after salvage ADT. Therefore, the patient underwent pelvic MRI, which detected recurrence of a suspicious lesion in the left lobe of the prostate. DWI showed high intensity and ADC showed low intensity in the lesion. Transperitoneal prostate saturation needle biopsy detected adenocarcinoma accompanied by neuroendocrine differentiation in the lesion (Fig. 2a). The serum level of NSE was 11.8 ng/mL (within the reference level). IHC findings of the tumor‐positive specimen showed negative PSA staining (Fig. 2b), positive AR staining (Fig. 2c), and positive SYP staining (Fig. 2d). No metastasis was detected in whole‐body CT and 99m‐Technetium‐Hydroxymethylene Diphosphonate Bone Scintigraphy. In April 2020, left hemi‐gland focal salvage iodine‐125 prostate brachytherapy was performed. The prescribed dose of the left hemi‐gland was 140 Gy. The delineation of CTV was based on the MRI image. To reduce the rectal dose, we utilized the hydrogel spacer. The postimplant dosimetry was performed a month after seed implantation (Fig. 3a), and it showed that the CTV D 90 (the minimal dose received by 90% of the volume) was 186Gy, the rectum V 100 (volume receiving 100% of the prescribed dose) was 0.01 cc, and the urethral V 150 (volume receiving 150% of the prescribed dose) was 0 cc. The biologically effective dose of the CTV was 198 Gy (Fig. 3b).

Fig. 1

Serum PSA levels and treatment course of this case. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 2

Representative images of H&E staining (a), IHC staining (×100) of PSA (b), AR (c), and SYP (d) of prostate biopsy specimens when local recurrence was detected; a high‐grade tumor defined by characteristic nuclear features, including lack of prominent nucleoli, nuclear molding, fragility, and high nuclear to cytoplasmic ratio accompanied by the signals of SYP in over 50% tumor cells. [Colour figure can be viewed at wileyonlinelibrary.com]

Fig. 3

The dose distribution in the post‐planning (a, b). The cyan line, white line, pink line, yellow line, dark green line, and blue line indicate the 100% dose distribution, the 150% dose distribution, the CTV, rectal spacer, urethra, and rectum, respectively. [Colour figure can be viewed at wileyonlinelibrary.com]

After the salvage brachytherapy, ADT was finished. Recurrence of a suspicious lesion in MRI has not been able to be detected for18 months. Serum PSA level slightly decreased and reached below the measurement sensitivity; <0.003 ng/mL. The patient had a PSA progression‐free survival of 20 months with no obvious adverse events.

Discussion

CRPC‐NE is one of the most aggressive prostate cancers. , CRPC‐NE arises after salvage ADT as a result of (i) lineage plasticity, (ii) differentiation from adenocarcinoma to a neuroendocrine tumor, and (iii) escape from AR pathway inhibition. , , , NEPC detection is difficult because no useful marker has been found so far. SYP, CgA, and CD56 are often used as neuroendocrine markers, but their sensitivity is low. In addition, serum PSA and PSMA do not help in NEPC detection. PSMA positron emission tomography/CT is useful for detecting small CRPC lesions but not NEPC.

In this case, MRI detected a small NEPC. DWI MRI detects a SCLC, which is neuroendocrine cancer. The ADC in SCLC is lower than that in benign lung tissue and NSCLC. Despite the limited papers on the MRI findings of NEPC, a study reported the MRI findings of 13 patients with histologically confirmed NEPC. Of these 13 patients, 3 were primarily diagnosed with small‐cell prostate cancer, and after endocrine therapy, 10 cases were considered a neuroendocrine type from being an adenocarcinoma. They demonstrated the NEPC as moderate low‐signal intensity in T2WI, high signal in DWI, and peak and wash‐out pattern in dynamic contrast‐enhanced imaging. The DWI finding is similar to this case. Similar to SCLC, compared with other types of imaging, MRI might be a better modality for NEPC detection.

The serum PSA values at NEPC diagnosis and PSA rise per month were reviewed in a retrospective analysis of 87 patients with histologically confirmed de‐novo NEPC or t‐NEPC. For patients with t‐NEPC, the average PSA rise and percent PSA rise per month before t‐NEPC biopsy diagnosis was 2 ng/mL and 16%, respectively. According to this analysis, the serum PSA level might have some importance in the follow‐up of t‐NEPC although other modalities such as MRI are needed. We measured NSE regularly during treatment, and it did not exceed the standard value.

NEPC is also resistant to both salvage ADT and AR‐targeted therapy, so cisplatin‐based chemotherapy is administered for metastatic cases instead of AR‐targeted therapy. In this nonmetastatic case, we performed focal therapy using salvage brachytherapy. Although the evidence for salvage focal brachytherapy in nonmetastatic CRPC recurrent after EBRT is limited, focal brachytherapy in this case did not result in either gastrointestinal or genitourinary adverse effect. In this case with nonmetastatic CRPC‐NE recurrent after radiotherapy, focal brachytherapy showed a good therapeutic effect and no adverse effects were observed, although long‐term follow‐up is needed.

Author Contributions

Takahiro Komori: Conceptualization; writing – original draft. Takeo Kosaka: Conceptualization; methodology; writing – review and editing. Keitaro Watanabe: Methodology; project administration; visualization. Tomoki Tanaka: Methodology; visualization; writing – original draft. Yota Yasumizu: Investigation; resources. Hiroshi Hongo: Methodology. Shuji Mikami: Methodology. Toshio Ohashi: Methodology. Mototsugu Oya: Supervision.

Conflict of interest

The authors declare no conflict of interest.

Approval of the research protocol by an Institutional Reviewer Board

The study was approved by the Institutional Ethics Board of Keio University Hospital (No. 20160084, 20180015).

Informed consent

Consent to participate and for publication were acquired from the patient.

Registry and the Registration No. of the study/trial

Not applicable.

Fig. S1. IHC staining (×100) of CgA; almost negative.

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