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Saidian, A.;  Dolendo, I.;  Sharabi, A.;  Stewart, T.F.;  Rose, B.;  Mckay, R.R.;  Bagrodia, A.;  Salmasi, A. Combination Radiation and Immunotherapy for Genitourinary Cancers. Encyclopedia. Available online: https://encyclopedia.pub/entry/39601 (accessed on 04 July 2026).
Saidian A,  Dolendo I,  Sharabi A,  Stewart TF,  Rose B,  Mckay RR, et al. Combination Radiation and Immunotherapy for Genitourinary Cancers. Encyclopedia. Available at: https://encyclopedia.pub/entry/39601. Accessed July 04, 2026.
Saidian, Ava, Isabella Dolendo, Andrew Sharabi, Tyler F. Stewart, Brent Rose, Rana R. Mckay, Aditya Bagrodia, Amirali Salmasi. "Combination Radiation and Immunotherapy for Genitourinary Cancers" Encyclopedia, https://encyclopedia.pub/entry/39601 (accessed July 04, 2026).
Saidian, A.,  Dolendo, I.,  Sharabi, A.,  Stewart, T.F.,  Rose, B.,  Mckay, R.R.,  Bagrodia, A., & Salmasi, A. (2022, December 30). Combination Radiation and Immunotherapy for Genitourinary Cancers. In Encyclopedia. https://encyclopedia.pub/entry/39601
Saidian, Ava, et al. "Combination Radiation and Immunotherapy for Genitourinary Cancers." Encyclopedia. Web. 30 December, 2022.
Combination Radiation and Immunotherapy for Genitourinary Cancers
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15010127

As the indications for the use of immunotherapy in genitourinary malignancies expand, its role in combination with standard or conventional therapies has become the subject of contemporary studies. Radiotherapy has multiple immunomodulating effects on anti-tumor immune response, which highlights potential synergistic role with immunotherapy agents. 

immunotherapy radiotherapy prostate cancer bladder cancer genitourinary malignancies

1. Introduction

Bladder and prostate cancer are among the most morbid and common malignancies in the US, respectively. Radiation therapy has been well-defined in the treatment of both malignancies. Radiotherapy is one of the principal strategies for bladder-sparing trimodal therapy for the treatment of bladder cancer. In the realm of prostate cancer, radiotherapy is utilized in treatment of localized and metastatic disease with curative, adjuvant, and palliative indications [1]. The role of immunotherapy in genitourinary malignancies has widely expanded in the past decade. Multiple checkpoint inhibitors have been approved for advanced bladder cancer including frontline use, maintenance post chemotherapy, and as second-line treatment. Additionally, immunotherapy combinations are being explored across all advanced disease states. Nivolumab was recently approved for the treatment of individuals with post-cystectomy bladder cancer who are at high risk for recurrence [2]. In contrast to bladder cancer, immunotherapy has a limited role in management of prostate cancer. While sipuleucel-T was the first autologous vaccine to prolong survival for prostate cancer, subsequent unselected immunotherapy strategies have been largely unsuccessful [3][4][5]. The only current indication for immune checkpoint inhibitors is in patients with high tumor mutational burden or microsatellite instability [6][7]. Along with approval of these agents, there is a growing body of evidence highlighting the potential synergistic role of combination immunotherapy and radiotherapy.

2. Radiotherapy in Combination with Immunotherapy in Bladder Cancer

Traditionally, the gold standard for treatment of muscle invasive bladder cancer (MIBC) was limited to chemotherapy and radical cystectomy. Recently, bladder-sparing trimodal therapy (transurethral bladder tumor resection followed by radiation and concurrent chemotherapy) has become a treatment option for MIBC [8]. Combination immunotherapy with radiation therapy in the management of bladder cancer is the primary subject of several ongoing clinical trials.
A phase II trial (NCT02662062) demonstrated satisfactory safety and promising efficacy of chemoradiotherapy (64 Gy in 32 daily radiation fractions) in combination with 6 weekly doses of cisplatin and concurrent pembrolizumab (200 mg IV q21 days for 7 doses) in 10 patients with MIBC [8]. The primary endpoint was feasibility, defined by a satisfactory low rate of unacceptable toxicity of grade 3 or 4 non-urinary adverse events or failure of completion of planned radiation therapy according to defined parameters. One patient had a dose of cisplatin withheld. Four of the ten patients experienced G3 – 4 non-urinary adverse events within 12 weeks of completing treatment. One immune-related adverse event interrupted pembrolizumab delivery (G2 nephritis). By week 24, 9/10 patients achieved a complete cystoscopic response to treatment and were free of distant metastatic disease. A similar multicenter phase II trial (NCT02621151) evaluated the safety and efficacy of pembrolizumab in addition to trimodal bladder preservation therapy (TMT) [9]. The study population was divided into a safety cohort (SC) and efficacy cohort (EC). Patients received pembrolizumab 200 mg × 1 followed 2–3 weeks by maximal TURBT and then whole bladder radiation (52 Gy/20 fx; IMRT preferred) with twice weekly gemcitabine 27 mg/m2 and pembrolizumab every 3 weeks for three treatments. The primary endpoint was 2 y bladder-intact disease-free survival (BIDFS: first of MIBC or regional nodal recurrence, distant metastases, or death) assessed by serial cystoscopy/cytology and CT/MRI. The estimated 1-year BIDFS rate is 77% (95% CI: 0.60–0.87). Twelve-week complete response rate was 100% in SC and 83% for EC. In the EC, 35% of patients had a ≥3 treatment-related adverse events (grade 3 events included UTI 8%, diarrhea 4%, colitis 4%, bladder pain/obstruction 4%, neutropenia 2%, and thrombocytopenia 2%). Pembrolizumab-related grade ≥3 adverse events included three patients (6%) with GI toxicity, of which one patient had a colonic perforation. One patient died due to fungemia, unrelated to the study therapy.
Ongoing studies are examining the role of combining immunotherapy with radiation for patients with bladder cancer. The phase II NUTRA trial (NCT03421652) is currently enrolling patients with non-MIBC for chemotherapy or cystectomy and administering nivolumab (240 mg IV q2 weeks for a maximum of 6 months) concurrently with SOC radiation therapy for bladder cancer [10]. A total radiation dose of 64 gray in 32 fractions was administered per standard of care for bladder cancer. If local lymph nodes were clinically involved, they had to be radiated. The primary outcome of the study is progression-free survival at 12 months and has yet to be reported. However, 6 of 14 patients have demonstrated a completed response: 4 had residual disease and 4 had disease progression. Nivolumab and radiation therapy toxicities were as expected: five patients needed steroids due to immune-mediated adverse events; diarrhea was observed in two patients; thyroid dysfunction was observed in two patients; and immune cystitis in was observed in one patient. No treatment related deaths were noted. A phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy preliminary reported safety and efficacy of combination treatment in patients with MIBC [11]. Treatment consisted of initial TURBT followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for three doses. Normofractionated external-beam radiation was started 2 weeks later, at doses of 46 Gy to minor pelvis and 64–66 Gy to bladder. A complete response at post-treatment biopsy was documented in 26 (81%) patients: 2 patients had residual MIBC, and 4 patients were not evaluated due to rejection, clinical impairment, death from COVID 19, and a suspected treatment-related death from peritonitis (one each). After a median follow up of 6.1 months (2.5–20.1), two patients underwent salvage cystectomy because of MIBC and T1 relapses. The estimated 6-month rates for disease-free survival (DFS) with bladder intact, DFS, and overall survival were 76% (95%CI, 61–5%), 80% (95%CI, 66–98%) and 93% (95%CI, 85–100%),. A total of 31 (97%) patients experienced adverse events related to radiation and/or immunotherapy, with diarrhea (41%) and urinary disorders (37.5%) as the most frequent. Grade 3 or 4 adverse events related to therapy were reported in 31% of patients, the most frequent being gastrointestinal toxicity (12.5%), acute kidney failure (6%), and hepatitis (6%). In another ongoing trial (NCT04936230), Himanshu et al. are evaluating the effect of stereotactic body radiation therapy (3 fractions over 2 weeks) in combination with atezolizumab in platinum ineligible/refractory metastatic urothelial cancer.
These results highlight the potential for radiation to synergize with immunotherapy in treatment of MIBC. However, checkpoint blockade immunotherapies are not intrinsic radiosensitizers and do not function primarily to enhance DNA damage from radiation. Currently, platinum-based chemotherapies remain the most effective radiosensitizers known, and, thus, caution should be taken when trying to replace platinum-based chemotherapies with immunotherapies. Alternatively, the use of immunotherapy after completion of a course of radiation or chemoradiation may be an advantageous strategy to enhance immune-mediated clearance after maximal tumor cytoreduction. The results from ongoing clinical trials are highly anticipated and will provide clinical evidence on how to best integrate immunotherapies with the current conventional modalities.

3. Radiotherapy in Combination with Immunotherapy in Prostate Cancer

There are a myriad of ongoing trials studying the role of combined radiotherapy and immunotherapy in prostate cancer. However, only a few RCTs have published results. A phase II trial randomized 49 patients with mCRPC to either sipuleucel-T alone or sipuleucel-T preceded by external-beam radiation therapy [12]. There was no statistically significant difference in progression free survival (p = 0.06) between the combination EBRT + sipuleucel-T arm (3.65 months) and the sipuleucel-T only arm (2.46 months). A single-arm phase II trial evaluated the utility of stereotactic ablative radiotherapy in addition to sipuleucel-T in patients with mCRPC. The median time to progression was 1.2 weeks (95% CI 6.8–14.0 weeks). [13] Unlike the phase II randomized trial combining EBRT and sipuleucel-T, this regimen did induce humoral and cellular immune responses. However, the immune response induced by stereotactic ablative radiotherapy did not yield a clinical benefit compared to previously reported outcomes of patients treated with sipuleucel-T.
A multicenter, randomized, double-blind phase III trial for men with mCRPC (with at least one bone metastasis) who had progressed on docetaxel randomized radiotherapy followed by ipilimumab (10 mg/kg q 3 weeks) vs. radiotherapy followed by placebo was reported by Kwon ED. et al [14]. The study was powered for a primary endpoint of overall survival. Unfortunately, in the initially report there was no significant difference in median overall survival of 11.2 months (95% CI 9.5–12.7) in the experimental arm versus 10.0 months (95% CI 8.3–11.0) in the placebo group; however, the p value was very close to significance at p = 0.053. In a subsequent subset analysis, there appeared to be a meaningful benefit to ipilimumab in men with a good performance status and absence of visceral metastases. Furthermore, in a recent pre-planned final analysis of this phase III trial, there was an excess of long-term survivors in the radiation plus ipilimumab arm with overall survival rates at 3 years and 5 years approximately two to three times higher in the radiotherapy + ipilimumab arm [15]. These data indicate that checkpoint blockade immunotherapies may have activity in a subset of men with prostate cancer and that additional biomarkers may be needed to guide precision medicine and identify those patients who are most likely to benefit from combinatorial therapies.

References

  1. Pinkawa, M.; Schoth, F.; Bohmer, D.; Hatiboglu, G.; Sharabi, A.; Song, D.; Eble, M.J. Current standards and future directions for prostate cancer radiation therapy. Expert. Rev. Anticancer Ther. 2013, 13, 75–88.
  2. Bajorin, D.F.; Witjes, J.A.; Gschwend, J.E.; Schenker, M.; Valderrama, B.P.; Tomita, Y.; Bamias, A.; Lebret, T.; Shariat, S.F.; Park, S.H.; et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N. Engl. J. Med. 2021, 384, 2102–2114.
  3. Handy, C.E.; Antonarakis, E.S. Sipuleucel-T for the treatment of prostate cancer: Novel insights and future directions. Future Oncol. 2018, 14, 907–917.
  4. Gardner, T.A.; Elzey, B.D.; Hahn, N.M. Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. Hum. Vaccin. Immunother. 2012, 8, 534–539.
  5. Wang, I.; Song, L.; Wang, B.Y.; Rezazadeh Kalebasty, A.; Uchio, E.; Zi, X. Prostate cancer immunotherapy: A review of recent advancements with novel treatment methods and efficacy. Am. J. Clin. Exp. Urol. 2022, 10, 210–233.
  6. Graf, R.P.; Fisher, V.; Weberpals, J.; Gjoerup, O.; Tierno, M.B.; Huang, R.S.P.; Sayegh, N.; Lin, D.I.; Raskina, K.; Schrock, A.B.; et al. Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer. JAMA Netw. Open 2022, 5, e225394.
  7. Mosillo, C.; Calandrella, M.L.; Caserta, C.; Macrini, S.; Guida, A.; Sirgiovanni, G.; Bracarda, S. Targeted Approaches in Metastatic Castration-Resistant Prostate Cancer: Which Data? Cancers 2022, 14, 4189.
  8. Weickhardt, A.J.; Foroudi, F.; Lawrentschuk, N.; Galleta, L.; Seegum, A.; Herschtal, A.; Link, E.; McJannett, M.M.; Liow, E.C.H.; Grimison, P.S.; et al. Pembrolizumab with chemoradiotherapy as treatment for muscle invasive bladder cancer: A planned interim analysis of safety and efficacy of the PCR-MIB phase II clinical trial (ANZUP 1502). J. Clin. Oncol. 2020, 38, 485.
  9. Balar, A.V.; Milowsky, M.I.; O’Donnell, P.H.; Alva, A.S.; Kollmeier, M.; Rose, T.L.; Pitroda, S.; Kaffenberger, S.D.; Rosenberg, J.E.; Francese, K.; et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. J. Clin. Oncol. 2021, 39, 4504.
  10. Vaishampayan, U.N.; Heilbrun, L.K.; Vaishampayan, N.; Li, C.; Shi, D.; Frazier, A.; Maier, J.; Dickow, B.; Kuettel, M.; Chatta, G.; et al. Phase II trial of concurrent nivolumab in urothelial bladder cancer with radiation therapy in localized/locally advanced disease for chemotherapy ineligible patients . Ann. Oncol. 2020, 31, S596.
  11. Muro, X.G.d.; Valderrama, B.P.; Medina, A.; Cuellar, M.A.; Etxaniz, O.; Sarrió, R.G.; Juan-Fita, M.J.; Ferrer, F.; Rodríguez, I.M.; Lendínez-Cano, G.; et al. Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy (RT) in patients (pts) with localized muscle invasive bladder cancer (MIBC) treated with a selective bladder preservation approach: IMMUNOPRESERVE-SOGUG trial. J. Clin. Oncol. 2021, 39, 4505.
  12. Li, C.; Jiang, P.; Wei, S.; Xu, X.; Wang, J. Regulatory T cells in tumor microenvironment: New mechanisms, potential therapeutic strategies and future prospects. Mol. Cancer 2020, 19, 116.
  13. Trapani, J.A. The dual adverse effects of TGF-beta secretion on tumor progression. Cancer Cell 2005, 8, 349–350.
  14. Colbeck, E.J.; Jones, E.; Hindley, J.P.; Smart, K.; Schulz, R.; Browne, M.; Cutting, S.; Williams, A.; Parry, L.; Godkin, A.; et al. Treg Depletion Licenses T Cell-Driven HEV Neogenesis and Promotes Tumor Destruction. Cancer Immunol. Res. 2017, 5, 1005–1015.
  15. Fizazi, K.; Drake, C.G.; Beer, T.M.; Kwon, E.D.; Scher, H.I.; Gerritsen, W.R.; Bossi, A.; den Eertwegh, A.; Krainer, M.; Houede, N.; et al. Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors. Eur. Urol. 2020, 78, 822–830.
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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Ava Saidian , Isabella Dolendo ,
Andrew Sharabi
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Tyler F. Stewart
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Brent Rose
, Rana R. McKay , Aditya Bagrodia , Amirali Salmasi
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Revisions: 2 times (View History)
Update Date: 03 Jan 2023
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