INTRODUCTION

Prostate cancer (PCa) is ranked as the second most common cancer and the fifth leading cause of cancerrelated deaths in men worldwide in 2018[1]. Unfortunately, some patients develop metastatic castrationresistant prostate cancer (mCRPC), including metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, studies have confirmed that apalutamide sustains a lower level of prostate-specific antigen(PSA) and improves the survival of patients with mHSPC. Several international guidelines recommend apalutamide as the standard treatment for mHSPC. During follow-up, PSA and radionuclide bone imaging are needed for systematic evaluation. Following the application of novel hormonal therapy,PSA was noted to decrease significantly in some patients after treatment. However, radionuclide bone imaging showed progression of bone metastases after 3 mo and with a gradual decrease noted during subsequent follow-up. Ryan

[2] calls this phenomenon “bone flare”. In this study, we retrospectively analyzed the "bone flare" phenomenon during apalutamide treatment in a patient with mHSPC. General information, clinical symptoms, laboratory and imaging examination, treatment, and follow-up data were collected and analyzed. We also share our experience regarding treatment of a patient who had the"bone flare" phenomenon during apalutamide treatment, and provide a reference for its clinical application.

CASE PRESENTATION

Chief complaints

The patient suffer lumbar pain for 1 mo.

History of present illness

On December 16, 2020, a 56-year-old man visited the outpatient clinic of the Department of Urology,Weifang People's Hospital, with a complaint of lumbar pain for 1 mo.

History of past illness

The patient had no relevant history of past illnesses.

Personal and family history

The patient has no relevant personal and family history.

Physical examination

There was nothing lacking that Valentine s Day after all. My father, in a voice quavering with emotion, read the loving message he d sent to my mother fifty-six years earlier. And this time, he could read it to her in person.

It s where he used to live. Gaston is out in the world and on his own now. You can see for yourself how comfortable he was in there. He had everything.

Laboratory examinations

Initial hormonal assay results were as follows: PSA > 100 ng/mL, ALP: 730 U/L. Ultrasound-guided needle biopsy of the prostate. Postoperative pathological results were as follows: poorly differentiated adenocarcinoma of the prostate, Gleason score: 5+4 = 9.

Imaging examinations

Magnetic resonance imaging (MRI) revealed a malignant mass in the peripheral zone of the prostate with multiple bone metastases. Radionuclide bone imaging revealed multiple bone metastases. Prostatespecific membrane antigen (PSMA) positron emission tomography – computed tomography (PET-CT)examination revealed PSMA aggregation in multiple bone sites.

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FINAL DIAGNOSIS

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

Digital rectal examination revealed a significantly enlarged, hard prostate with palpable non-tender nodules on the left side.

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TREATMENT

When apalutamide therapy is used in the treatment of prostate cancer, an increase in metastatic bone lesions on radionuclide bone imaging and MRI; warrants the use of other examinations including PSA,PSMA PET-CT, to determine the efficacy of ongoing treatment, so as to determine the course of treatment for such patients.

OUTCOME AND FOLLOW-UP

The authors declare that they have no conflict of interest.

DISCUSSION

In most patients diagnosed with prostate cancer with distant metastases at the clinic, bone metastasis is the most common. Studies have shown that androgen receptors (AR) play an important role in the development of prostate cancer[3]. Therefore, ARs are an important target for the treatment of prostate cancer. However, with prolonged conventional AR-targeted drug therapy, patients with prostate cancer experience a reduction in therapeutic effect[4]. Presently, research and development of new ARtargeting drugs has become a hotspot in the field of prostate cancer treatment.

Apalutamide, an oral non-steroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor and prevents androgen receptor translocation, DNA binding, and androgen receptor–mediated transcription[5], has shown good efficacy and safety in clinical practice.The 2020 EAU prostate cancer guidelines recommend ADT in combination with apalutamide and enzalutamide, a new generation of androgen receptor antagonists, as first-line therapy for metastatic prostate cancer. Ryan

[2] reported that after abiraterone treatment for 3 mo, the PSA level decreased by more than 50%, but bone metastasis lesions increase. Furthermore, after 6 mo of continued treatment,bone scan revealed reduced or stable lesions, and this was termed the “bone flare” phenomenon. During treatment, the laboratory results of patients with the bone flare phenomenon showed no significant change in the alkaline phosphatase level, however, PSA level continued to decrease. Our case revealed that bone flare phenomenon also occurs with apalutamide therapy. Some studies have also shown that bone flare occurs in some breast cancer patients with bone metastasis after chemotherapy and other treatments, and is considered to be a sign of effective treatment of bone metastases. Cook

[6]reported that of 22 patients with unequivocal skeletal metastases on baseline scan, flares occurred in 9(41%). Out of 36 high-risk localized prostate cancer patients with normal pre-treatment bone scintigraphy, the scan became positive for metastases at 6 wk in 4 (11%). Furthermore, out of 41 patients, pretreatment scintigraphic abnormalities of uncertain etiology and flares occurred in 8 patients (20%).

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

Therefore, during the novel hormonal therapy in mHSPC patients with bone metastasis, it is important to identify whether the treatment is ineffective or whether the bone flare phenomenon is observed when bone scan indicates bone disease progression. This will determine the subsequent treatment strategy for patients. If PSA levels are not reduced after treatment and clinical symptoms worsen, the possibility of disease progression should be considered, and a new treatment strategy should be selected. Otherwise, bone flare should be considered if the PSA level decreases significantly after treatment, and the patient's clinical symptoms improve significantly. In this case, the original treatment was maintained with close follow-up. Bone scan showed increased metastases, but the PSA level decreased significantly. Following PSAM, PET-CT results showed significant improvement in bone metastasis, and the bone flare phenomenon was confirmed.

CONCLUSION

Androgen deprivation therapy (ADT) using novel hormonal therapy (goseraline sustained-release implant 3.6 mg monthly and apalutamide 240 mg/d was initiated on December 24, 2020.

FOOTNOTES

Li KH reviewed the literature, and contributed to manuscript drafting; Du YC, Yu XY and Li YX contributed to manuscript drafting; Zhang XP and Yang DY obtained informed consent; Qiao L was responsible for the revision of the manuscript; and All authors gave final approval for the submitted version.

Based on the results obtained from imaging and histopathology, the final diagnosis was prostate adenocarcinoma (T

N

M

).

PSA levels and alkaline phosphatase levels were reviewed monthly, and imaging examinations were reviewed every three months. The PSA level decreased significantly during the treatment; however,three months later, radionuclide bone imaging and MRI indicated progression of the bone metastasis(Figure 1). Contrarily, PSMA PET-CT examination showed significantly decreased PSMA aggregation on the bone, indicating improved bone metastases (Figure 2). Considering that the lumbar pain, which he initially presented with, continued to decrease, the treatment strategies were considered to be effective. The original treatment strategies were continued for over 4 mo. The patient's PSA decreased to normal levels (Figure 3), and his clinical symptoms reduced significantly; therefore, treatment was continued.

In the present study, the patient was diagnosed with mHSPC and bone metastasis. The initial treatment strategy was ADT and apalutamide. However, bone flares occurred 3 mo after treatment, and a bone scan showed metastatic progression. However, PSMA PET-CT examination showed that abnormal PSMA aggregation was significantly reduced, and bone metastasis was significantly improved compared to the baseline. Therefore, the temporary phenomenon of increased lesions in the bone scan was considered a bone flare. During treatment, the PSA level decreased significantly, and the alkaline phosphatase level did not change significantly. Vincenza

[7] pointed out that therapy for metastatic disease may lead to healing and new bone formation, which causes an initial increase in tracer uptake (akin to callus formation). This deterioration, followed by subsequent improvement in the bone scan appearance after successful therapy, is defined as a flare response. Due to the shortcomings of the current assessment based on PSA and imaging examinations, more research results show that the changes in the number of circulating tumor cells in peripheral blood can be used as a new means of evaluating efficacy. If the treatment is effective, the number of circulating tumor cells will decline rapidly. The increase or decrease in the number of circulating tumor cells after treatment is also a predictor of patient survival. The prognostic value is significantly better than PSA and imaging examination[8,9]. In the latest PCWG3 study, assessment of circulating tumor cell number was used as an important marker for disease evaluation and to assess drug efficacy[10].

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Ke-Hao Li 0000-0003-2467-6526; Yuan-Cheng Du 0000-0003-2116-5202; Dong-Yu Yang 0000-0002-2194-9878; Xin-Yuan Yu 0000-0003-3147-5474; Xue-Ping Zhang 0000-0001-9245-8833; Yong-Xiang Li 0000-0002-5196-8113;Liang Qiao 0000-0002-7258-0484.

Little boys make too much noise. They d scare the fish, being shouters and laughers and slappers. They d muddy the water, and leave gum wrappers. No -- I d be a fool to let them fish in my pool.

He is like one of the family, faithful and grumpy; but the latter is my grandchildren s fault, for they have teased him; they play at wedding, and want to give him the part of the bridesmaid, and that s too much for him, poor old fellow

Ma YJ

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Ma YJ

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