Efficacy of Combined Pembrolizumab and Pelvic Radiotherapy for Bladder Cancer With Rectal Metastases

Abstract

Background/Aim: Rectal metastases from urothelial carcinoma (UC) are extremely rare with poor prognosis when treated with gemcitabine and cisplatin (GC) chemotherapy, radiation therapy, and total pelvic exenteration. Long-term survival has not been observed in patients treated with GC chemotherapy, radiation therapy, or total pelvic resection. However, there have been no reports on the efficacy of pembrolizumab therapy for this specific condition. Herein, we describe a case of rectal metastasis from UC, treated with combined pembrolizumab and pelvic radiotherapy.

Case Report: A 67-year-old male patient with an invasive bladder tumour underwent robot-assisted radical cystectomy and ileal conduit diversion followed by neoadjuvant GC chemotherapy. The pathological findings showed high-grade UC, pT4a, with a negative surgical margin. He presented with an impacted ileus due to severe rectal stenosis on postoperative day 35 and underwent a colostomy. Pathologically, rectal biopsy confirmed rectal metastasis; thus, the patient was started on pembrolizumab 200 mg every 3 weeks and pelvic radiotherapy with a total dose of 45 Gy. The rectal metastases remained well controlled with stable disease status, and no adverse events were observed 10 months after the initiation of combined pembrolizumab and pelvic radiotherapy.

Conclusion: Pembrolizumab combined with radiation therapy may be an alternative treatment for rectal metastases from UC.

Bladder tumours commonly metastasize to the regional lymph nodes, liver, lung, and bone. Although these may involve the distal gastrointestinal tract, they are most commonly caused by direct invasion; hence, non-contiguous metastases are rare (1). Rectal metastases from urothelial carcinoma (UC) are extremely rare and have a poor prognosis (2). Several reports have described bladder cancer with rectal metastases treated with gemcitabine-cisplatin (GC) chemotherapy, radiation therapy, and total pelvic exenteration. However, long-term survival was not observed in these cases (3-5).

The Keynote045 trial confirmed the effectiveness of pembrolizumab as a second-line therapy for metastatic or advanced UC (6). However, there have been no reports of pembrolizumab use for rectal metastases from bladder cancer. Herein, we report a case of bladder cancer with rectal metastases successfully managed with combined pembrolizumab and pelvic radiotherapy after radical cystectomy.

Case Report

A 67-year-old man presented with gross haematuria and was admitted to a nearby hospital. Ultrasonography and magnetic resonance imaging revealed a bladder tumour. He underwent transurethral resection of the bladder tumour, and pathological findings showed UC, pT2, G3>G2 high-grade. After two cycles of neoadjuvant GC chemotherapy, the patient was referred to our institute for radical surgery, where he subsequently underwent robot-assisted radical cystectomy with bilateral pelvic lymph node dissection and ileal conduit diversion. Histopathological examination confirmed UC, pT4a, negative surgical margins, and no lymph node metastases. The patient was discharged on postoperative day (POD) 15 without any complications. However, on POD 35, he was readmitted to our hospital emergently due to ileus with severe constipation and anal pain. Digital rectal examination revealed severe stenosis. Tumour markers, including carcinoembryonic antigen and carbohydrate antigen 19-9, were within the normal ranges. The colonoscope could not pass through the rectum (Figure 1A), and a computed tomography (CT) scan confirmed extensive thickening of the surrounding tissue (Figure 1B and C). Subsequently, transverse colostomy was performed on POD 39, and pathological findings on rectal biopsy revealed UC. Immunohistochemically, the tumour cells stained positive for GATA3 with high molecular weight cytokeratins (HMW-CK) and negative for CDX2, which is not a typical pattern of primary rectal cancer. Based on these results, a diagnosis of rectal metastasis from bladder cancer was made.

Figure 1. Colonoscopy and computed tomography findings prior to pembrolizumab treatment. Colonoscopy showing a granular prominence a few centimetres from the anal verge and a stenosis (A). Sagittal (B) and transverse (C) computed tomography showing circumferential thickening of the rectal wall.

Retrospective examination of the CT scan performed after neoadjuvant GC therapy revealed that slight rectal wall thickening could already be seen, which was considered to be disease progression during neoadjuvant GC therapy; thus, we selected pembrolizumab as second-line therapy.

The patient was started on pembrolizumab 200 mg every 3 weeks and pelvic radiotherapy with a total dose of 45 Gy. After four courses of pembrolizumab, the anal pain resolved, and the CT scan showed no exacerbation of rectal metastases, suggesting stable disease (SD). The rectal metastases remained controlled on SD status, and no adverse events were observed 10 months after the initiation of pembrolizumab therapy.

Discussion

It is common for invasive bladder cancer to metastasize to the regional lymph nodes, liver, lung, and bone, with further invasion to the muscular layer or the bladder surface. However, it is extremely rare for bladder cancer to progress to the rectum (1,2). There are three hypotheses to explain the mechanism underlying the metastasis of bladder tumours to the rectum. First, it could be due to a previous iatrogenic exposure-caused deposition. Second, the direct invasion may be caused by penetration of the bladder wall via Denonvilliers’ fascia to the rectum. Lastly, metastasis could spread via the lateral pedicles of the bladder to the posterior rectal wall, subsequently resulting in wall infiltration (2). In the present case, the pathological diagnosis was negative for surgical margins, but the vascular invasion was positive; hence, we hypothesized that the tumour may have metastasized or disseminated.

We summarized several case reports of bladder cancer with rectal metastasis (Table I) (2-5,7-12). From 2002 to 2021, 12 cases of UC metastasis to the rectum, including the present case, have been reported. The mean time to rectal metastasis after initial therapy was 15.7 months (range=1-48 months) for 11 cases and unknown for one case. One patient was treated with total pelvic exenteration; colostomy was performed in 8 cases, radiotherapy in 4 cases, and chemotherapy was performed in 6 cases, which included GC, M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin), and unclear regimens. Only one case, treated with a colostomy, chemotherapy, and radiotherapy, had a long survival time after treatment (12). None of the patients was treated with pembrolizumab. To the best of our knowledge, our case is the first report of bladder cancer with rectal metastases treated with pembrolizumab and pelvic radiotherapy that was well controlled with SD status.

Table I. Previous case reports of bladder cancer with rectal metastases.

*TNM at initial diagnosis of urothelial carcinoma. BCG: Bacille de Calmette et Guérin; GC: gemcitabine and cisplatin; M: male; MVAC: methotrexate, vinblastine, doxorubicin, and cisplatin; RC: radical cystectomy; SD: stable disease; TUR-Bt: transurethral resection of bladder tumour.

The use of Pembrolizumab as a second-line treatment can allow significantly improved overall survival in patients with locally advanced or metastatic UC as compared to standard-of-care chemotherapy, as shown in the Keynote 045 trial (6). However, the effectiveness of pembrolizumab for rectal metastasis from UC has not yet been discussed. We estimated the effectiveness of pembrolizumab combined with radiotherapy for rectal metastasis of bladder cancer from two perspectives. First, the rectal metastasis was radiographically well controlled as SD status on enhanced CT. Although the average survival time after rectal metastasis is reported to be approximately 5 months (10), in the present case, the SD status has been controlled for 10 months using pembrolizumab. Second, the patient’s anal pain remarkably improved. Before treatment, anal pain was approximately 7/10 on the Numerical Rating Scale (NRS) even with tramadol hydrochloride and acetaminophen; however, after treatment, the NRS score was reduced to 2/10 without the use of analgesics. Vassiliou et al. concluded that RT has the potential to synergize with immunotherapy to improve oncological outcomes in patients with localized or metastatic bladder cancer, and Palliative RT in the form of external beam irradiation in combination with chemotherapy, targeted therapies and, more recently, immunotherapy, offers palliation and relief from symptoms (13).

The results of this case suggest that pembrolizumab combined with radiation therapy for patients with rectal metastasis from UC can help to effectively manage the disease. It is necessary to study multiple cases of rectal metastasis of bladder cancer treated with pembrolizumab combined with radiation therapy.

Conclusion

We report a case of rectal metastasis from UC treated with pembrolizumab combined with radiation therapy. Although further verification is needed, pembrolizumab could be an effective treatment for rectal metastasis from UC.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

CN wrote the manuscript and provided the table and figure. JI, KY, RM, HF, KY, HO, HI, YN, and TT cared for the patient and administered pembrolizumab in combination with radiation therapy. All Authors have read and approved the final manuscript.

Acknowledgements

The Authors would like to thank Ms. Nobuko Hata (Department of Urology, Tokyo Women’s Medical University) for her secretarial work.