Bladder sparing by short-course radiotherapy combined with toripalimab in high-risk/extremely high-risk non-muscle invasive bladder cancer (HOPE-04): study protocol for a single-arm, prospective, phase II trial

Abstract

Introduction

Radical cystectomy remains the standard treatment for intravesical Bacille Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC) because potential bladder-preserving therapies are not well established. Combination of radiotherapy with programmed death-1 (PD-1) antibody may offer an optional bladder preservation treatment for high-risk/extremely high risk NMIBC. Hence, the current study aims to investigate the safety and efficacy of short-course radiotherapy (5×5 Gy) and toripalimab (PD-1 antibody) as a novel bladder sparing treatment in this population.

Methods and analysis

HOPE-04 is an open-label, single-arm, phase II study, designed to evaluate the safety and efficacy of short-course radiotherapy and toripalimab in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will be recruited. Radiotherapy of 5×5 Gy will be given to the whole bladder followed by a focal tumour bed boost and concomitant administration of toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about 1 year). The primary endpoints are disease-free survival and safety. The secondary endpoint is overall survival. Additional indicators include implementation rate of salvage surgery and quality of life.

Ethics and dissemination

This trial has been approved by the Ethics Committee of West China Hospital, Sichuan University. Trial findings will be disseminated via peer reviewed journals and conference presentations.

Trial registration number

Chinese Ethics Committee of Registering Clinical Trials (ChiCTR2200059970).

Correspondence to Yali Shen; [email protected]

Strengths and limitations of this study

• HOPE-04 is the first attempt of short-course radiotherapy and toripalimab combination in the bladder sparing treatment of high-risk/extremely high risk non-muscle invasive bladder cancer (strength).

• HOPE-04 extends the therapeutic options of bladder preservation treatment for this population (strength).

• The prevention effect of local recurrence as well as distant metastasis will be investigated, and toxicities as well as quality of life will be evaluated (strength).

• The patient sample is limited in the current phase II trial single-arm study, and the results need to be verified in further randomised, multicentre phase III trial with larger sample size (limitation).

Background

Bladder cancer is a commonly diagnosed malignancy all over the world, and it is more common in men than in women, with estimated incidence rate and mortality rate ranking fourth and eighth among all cancer types in the US men in 2023, respectively.^{1 2} Approximately two-thirds of newly diagnosed bladder cancer belong to non-muscle invasive bladder cancer (NMIBC), and the risk of recurrence rate approaches 80% and the risk of progression to muscle-invasive disease is 50%–65% if only transurethral resection of the bladder tumour (TURBT) is applied.^3–5 Therefore, intravesical therapy with Bacille Calmette-Guerin (BCG) after TURBT is recommended as standard adjuvant treatment to decrease the overall recurrence rate about 30%.⁶ However, nearly 15%–40% patients still suffer from tumour progression within 5 years, which are at risk of dying from urothelial bladder cancer.⁷ Radical cystectomy remains the standard treatment for intravesical BCG unresponsive NMIBC, which is not feasible when patients have the competing comorbidities or desire for bladder preservation. However, even novel intravesical therapies, such as combination chemotherapy, oncolytic adenovirus, interferon, have shown limited efficacy and potential bladder-preserving therapies are still not well established until now.^{8 9}

The role of radiotherapy in NMIBC has been explored in clinical practices for several decades. Weiss et al demonstrated that 88% of patients with high risk T1 (T1HR) bladder cancer receiving radiotherapy or platinum-based chemoradiotherapy after TURBT achieved complete response (CR). Among those who achieved CR, the 5-year and 10-year disease specific survival were 89% and 79%, respectively, of which more than 80% of patients had retained their bladder and 70.4% of patients were satisfied with their bladder function after radiotherapy. Therefore, radiotherapy after TURBT might be a good alternative treatment strategy for patients with T1HR bladder cancer with intravesical and early cystectomy, which was safe and the adverse effects were controllable.⁷ A meta-analysis published in Urol Oncol in 2021 included 746 patients with high-risk NMIBC receiving radiotherapy in 13 studies, namely, high-grade T1, T1/Ta with associated risk characteristics including carcinoma in situ (CIS), multifocal, diameter >5 cm and/or multiple. And radiotherapy showed local disease control effect in these patients with NMIBC with 13% salvage cystectomy and 9% distant metastasis. The study demonstrated radiotherapy would be a bladder preservation treatment for NMIBC, which needed further prospective trials to verify.¹⁰

In recent years, immunotherapy has revolutionised the treatment of urothelial bladder cancer. Based on the KEYNOTE-057 (NCT02625961) study results of cohort A, pembrolizumab is recommended by National Comprehensive Cancer Network (NCCN) guidelines as a non-cystectomy option for patients with NMIBC with BCG unresponsive, especially for patients with CIS.¹¹ However, according to American Society of Clinical Oncology Genitourinary Cancers Symposium updated data in 2021, in cohort A of patients with CIS, 50.9% of patients who did not achieve CR still received cystectomy and 44% of patients who relapsed after CR chose radical cystectomy for subsequent treatment. And in patients with papillary NMIBC of cohort B, the median disease-free survival (DFS) was 7.7 months (95% CI, 5.5 to 13.6) and 43.5% patients maintained no evidence of disease at 12 months. More than half of the patients suffered from local disease recurrence. Therefore, pembrolizumab as a systemic treatment cannot reduce the risk of patients undergoing radical cystectomy significantly, and it is urgent to explore other effective treatments in combination to achieve the goal of bladder preservation.

Immunotherapy and radiotherapy have been proven to have synergistic mechanisms for many cancers, and early study showed that the combination treatment could not only enhance tumour killing ability locally but also control disease distantly though abscopal effect.¹² And the combined effects have been successfully explored in patients with MIBC bladder preservation treatment.^{12 13} Several phase II studies of immunotherapy combined with concurrent radiotherapy for bladder sparing treatment in MIBC showed that the 1-year bladder sparing DFS were 76%–89%.^{14 15} Therefore, the role of the systemic and local treatment mode of immunotherapy combined with radiotherapy in patients with high-risk NMIBC is also worth exploring.

Currently, most of the ongoing trials about the radiotherapy and immunotherapy combination in NMIBC are focused on conventional fractionated radiotherapy. Usually, it takes patients more than 2 months to finish the radiotherapy, which is a challenge for their compliance. As urothelial carcinoma is sensitive to radiotherapy, there is still room for further optimisation of different fractions of radiotherapy. In 2018, Tree et al explored the safety and efficacy of 36 Gy/6 f radiotherapy combined with pembrolizumab immunotherapy in locally advanced MIBC (PLUMMB trial), but the study was terminated early due to five patients meeting dose limiting toxicity. In this trial, the ‘priming’ dose of pembrolizumab was given prior to the radiation initiating, which might induce a more inflamed urothelial environment to develop serious local toxicity.¹⁶ Based on this trial, more reasonable hypofraction radiotherapy modes have been further explored in ongoing trials in MIBC, including 52 Gy in 20 fractions combined with pembrolizumab and gemcitabine (NCT02621151), 65 Gy in 35 fractions or 55 Gy in 20 fractions combined with avelumab (NCT03747419) and the results are not reported. Besides, recently in a phase I trial showed that immunotherapy combined with external beam radiation therapy (18 Gy in 3 fractions in cycle 1 only) in NMIBC was well tolerated and favoured a longer duration of response, and the 12 CR rate was 33%, which needed further improvement.¹⁷ Although there are several clinical studies about hypofractionation in bladder cancer, there is still no specific recommendation for segmentation methods until now.

As we know, the most mature method currently used in pelvic radiotherapy is 25 Gy/5 f, especially in radiotherapy for rectal cancer, effectiveness and safety of which have been confirmed by multiple studies (Polish II, RAPIDO and STELLAR study).^18–20 In these studies, as a normal organ, the safety of bladder either partial or complete irradiation has also been confirmed. In Timmerman’s 2011 version of the recommended dose limit for organs at risk (OAR) of large fractionated radiotherapy, the maximum dose limit for the bladder in 5 fractions is 38 Gy.²¹ Therefore, we plan to explore the combination of 25 Gy/5 f radiotherapy and immunotherapy as a bladder preservation for NMIBC. Besides, based on the systematic review and meta-analysis of radiation therapy for high-risk NMIBC, the bladder radiation dose was approximately 50 Gy, which was lower than that of MIBC.¹⁰ Hence, a focal tumour bed boost of 9–18 Gy in 3–6 fractions will be given sequentially after the whole bladder radiation to ensure the dose is enough for bladder cancer.

Therefore, this study intends to conduct an II study to explore the efficacy and safety of programmed death-1 (PD-1） monoclonal antibody (toripalimab) combined with short-course radiotherapy of 25 Gy/5 f followed by a focal tumour bed boost in patients with high-risk or extremely high-risk NMIBC with bladder sparing will.

Materials and methods

Patient and public involvement statement

Patients or the public were not involved in the design, conduct, reporting or dissemination plans of this research. The findings will be disseminated by peer-reviewed journals or conference presentations.

Protocol version

Protocol V.2.0, modified on 15 January 2023.

Study design

The current prospective phase II, open-label, single-arm study, designs to evaluate the safety and efficacy of short-course radiotherapy (25 Gy in 5 fractions) followed by a focal tumour bed boost and toripalimab as a novel bladder sparing treatment in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will receive total TURBT. Then radiotherapy of 25 Gy in 5 fractions will be given to the whole bladder every other day and concomitant administration of toripalimab of 240 mg intravenous infusion every 21 days for 12 cycles (about 1 year). The boost radiotherapy will be given to the focus based on the location of the disease, the findings of TURBT, pathological components and condition of neighbour organs and the dose usually is 9–18 Gy in 3–6 fractions. Treatment efficacy will be performed by CT and MRI, transurethral multipoint biopsy and urine cytology. The flow-chart of the study is presented in figure 1.

Figure 1. The flow-chart of the HOPE-04 study. EORTC QLQ-C30 V3.0, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 vesion 3.0; FACT-BL, Functional Assessment of Cancer Therapy-Bladder Cancer; FACT-G, Functional Assessment of Cancer Therapy-General; DFS, disease-free survival; NMIBC, non-muscle invasive bladder cancer; OS, overall survival; TURBT, transurethral resection of the bladder tumour.

Study organisation and drug supply

The current trial is principal-investigator mainly initiated by a single centre of West China Hospital, Sichuan University. Signed informed consent is required before an eligible patient is enrolled. Toripalimab is provided free of charge by Shanghai Junshi Biomedical Technology. for clinical trial subjects. The study was started in February 2023, and the planned end date for the patients recruiting is February 2025.

Study population

According to the NCCN guidelines V.2022. V1, high risk NMIBC includes high grade urothelial carcinoma with CIS or T1 or >3 cm or multifocal; and very high-risk features includes (any) BCG unresponsive, variant histologies, lymphovascular invasion and prostatic urethral invasion. Patients with pathological and imaging diagnosed high-risk or extremely high-risk NMIBC will be selected according to the inclusion criteria and exclusion criteria. For patients with active autoimmune disease or immunodeficiencies, organ transplantation history or systematic use of immunosuppressive drugs or contraindications for pelvic radiotherapy will be excluded (table 1). All the participants will receive total TURBT first. And whether BCG unresponsive and programmed death-ligand 1 (PD-L1) expression can be analysed as stratify factors.

Table 1

Inclusion and exclusion criteria

Patients should have the ability to choose treatment independently, and sign the written informed consent. Male or female, who has reached the age of 18 on the date of signing the informed consent. Non-myometrial invasive urothelial carcinoma confirmed by cystoscopy and histology. High-risk/extremely high risk NMIBC. Willing to retain bladder, with good bladder function (bladder volume at least 300 mL). All patients must undergo complete TURBT and results of urine fish/urine exfoliated cells after TURBT are negative. Sufficient functions of heart, bone marrow, liver, kidney and other organs: Neutrophils ≥1.5 x 10∧9/L. Haemoglobin ≥90 g/L (concentrated red blood cells were not infused within 2 weeks). Platelet ≥100x10∧9/L. Glutamic pyruvic transaminase ≤2.5×, glutamic oxaloacetic transaminase ≤2.5×ULN. Total serum bilirubin ≤1.5×ULN. Blood creatinine ≤1.5×ULN, or serum creatinine clearance rate ≥50 mL/min. Normal or abnormal coagulation function (PT, APTT, TT, FBG) has no clinical significance: Life expectancy exceeds 12 months. ECOG physical condition: 0 or 1 point. Willing and able to follow the study and follow-up procedures.

Patients who have received pelvic radiotherapy. There are active or progressive infections requiring systematic treatment, such as active tuberculosis, active hepatitis. There are systematic diseases judged by researchers to be unstabilised, including diabetes, hypertension, cirrhosis and severe lung diseases. Pregnant or lactating women. Suffering from any other disease, metabolic abnormality, abnormal physical examination or abnormal laboratory examination. And according to the judgement of the investigator, it is reasonable to suspect that the patient has a disease or state that is not suitable for the use of the study drug, or will affect the interpretation of the study results, or put the patient at high risk. The compliance of patients participating in this clinical study is insufficient. After complete TURBT, the results of urine fish/urine exfoliated cells were more than 2 months.

APTT, activated partial thromboplastin time; ECOG, Eastern Cooperative Oncology Group; FBG, fibrinogen; NMIBC, non-muscle invasive bladder cancer; PT, Prothrombin time; TT, thrombin time; TURBT, transurethral resection of the bladder tumour.

Study endpoints and assessment

The primary endpoints are DFS and safety. The secondary endpoint is overall survival (OS), and other observation indicators include implementation rate of salvage surgery and quality of life. Imaging evaluation will be performed based on the Response Evaluation Criteria in Solid Tumours (RECIST V.1.1) and immune Response Evaluation Criteria in Solid Tumours. As all the patients will receive total TURBT, the lesions will be completely resected. Hence, 1-year DFS is applied as the primary endpoint, which is defined as undetectable tumour existence by chest and abdominal CT, bladder MR and no evidence of tumour cells in cystoscopy of multipoint biopsy and urine cytology. Safety is another main endpoint. Adverse effects will be evaluated every cycle of treatment and recorded according to the Common Terminology Criteria for Adverse Events V.4.0 and radiation therapy oncology group criteria. The study will be terminated if five patients of the first six-patient suffer from any therapy-associated grade 3 and above toxicity occurring within the first 12 weeks after the completion of radiotherapy except for grade 3 hypothyroidism. OS is defined as time from enrolment to death. At the same time, local recurrence-free survival (LRFS) and distant-metastasis-free survival (DMFS) will be recorded, defining as time from evidence of no existence of tumour to local recurrence or distant metastasis of disease per RECIST V.1.1 or death, respectively. And the implementation of salvage surgery will be evaluated. Patients’ quality of life will be estimated based on European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL), and Functional Assessment of Cancer Therapy-General (FACT-G) scale at the end of the radiotherapy and during every follow-up visit.

Sample size

The main endpoint of this trial is to evaluate the DFS rate. Based on previous study, the 12-month disease-free rate of BCG for patients with high-risk NMIBC is about 65%.²² Hence, the p0 value was 65%, and the expected 12-month disease-free rate reaches (p1): 80%. Assuming bilateral a=0.05, β=20%, according to Simon’s second stage calculation, a total of 55 patients need to be included, namely, 31 patients in the first stage and 24 patients in the second stage. If there are more than 20 patients in the first stage without recurrence or metastasis within 12 months, they will enter the second stage for enrolment. The planned enrolment period is 1–2 years. Considering the interference of other factors, we will include as many patients as possible who meet the inclusion criteria.

Treatment dose

The application of 5×5 Gy to the rectum was reported in several studies, including Polish II (over 5 days), RAPIDO (no more than 8 days) and STELLAR (over 1 week).^18–20 The style of radiotherapy being delivered varies with different study centres. And in our centre, the 5×5 Gy is delivered every day or every other day, hence 5–10 days in total are needed. And a focal tumour bed boost of 9–18 Gy in 3–6 fractions is given sequentially after the whole bladder radiation. Based on a systematic review and meta-analysis of radiation therapy for high-risk NMIBC, the bladder radiation dose is approximately 50 Gy, which is lower than that of MIBC.¹⁰ Hence, the effect of 5×5 Gy and 9–18 Gy in 3–6 fractions combination is supposed for bladder preserving in NMIBC. And the boost volume is based on the primary lesion of imaging before TURBT.

Radiotherapy planning and delivery

Before radiotherapy planning CT scan, patients are required to have an empty bladder and encouraged to evacuate their bowels of flatus and faeces. And no drinking for 30 min before planning a CT scan. Gross tumour volume (GTV) is countered with the aid of all the diagnostic imaging (CT and MRI) before TURBT to include the primary tumour bed, and clinical target volume (CTV) should be carried out to encompass the GTV and the whole bladder. Isotropical expansion of 1.0–1.5 cm of CTV is planning target volume (PTV) and RayStation is a treatment planning system. Stereotactic body radiotherapy planning technique is recommended, and intensity modulated radiotherapy or volumetric modulated arc radiotherapy treatment is allowable. All the treatment plans are made to ensure at least 98% of the PTV to receive no less than 95% of the prescribed dose and the maximum is no more than 107% of the prescribed dose. To avoid the high dose outside the PTV, 1 cm³ of the normal tissue outside the PTV is required to receive no more than 110% of the prescribed dose. Besides, the dose to the OAR is encouraged to be as low as possible, dose volume constraints of which are summarised in table 2.

Table 2

Organ at risk dose constraint

Phase	Organ at risk	Volume	Volume max (Gy)	Max point dose (Gy)
5*5 Gy phase*	Colon	<20 cm3	32.5	52.5
	Rectum	<3.5 cm3 <20 cm3	50 37.5	55
	Bladder wall			38
	Femoral heads	<10 cm3	30
Total	Rectum	<10 cm3	60

*Timmerman table, 2021.

Follow-up

Based on the study protocol, patients will receive regular examinations at the baseline and at every visit during the treatment and follow-up. Regular examinations consist of chest and abdominal CT, bladder MR, cystoscopy of multipoint biopsy, urine cytology, blood cells counting, liver and kidney function test, urine routine test. The evaluation time is every 3 months in the first 2 years, every 6 months in the next 3 years and once every year later.

Data collection, management and monitoring

This is an investigator-initiated trial, and the data collection and management will be completed by researchers. Because the current study is initiated by bladder multidisciplinary treatment (MDT), the treatment efficacy evaluation will be conducted by surgeons, oncologists, imaging physicians, ultrasound physicians and pathologists and so on from the MDT members to ensure the reliability of the results. The data of the participants in the study will be kept confidential and be anonymous.

Statistical analysis

SPSS V.2021 will be applied for statistical analysis. Fisher’s exact test can be used to compare the patient characteristics between stratify factors. DFS, OS, LRFS and DMFS will be estimated with the application of Kaplan-Meier method. A stratified log-rank test will be used to do survival comparations. P value<0.05 is regarded as significant for two-sided statistical tests.

Discussion

The standard treatment for high risk NMIBC is TURBT followed by BCG intravesical therapy. It is known that the prognosis is poor for BCG unresponsive patients, and radical cystectomy is recommended.²² Some of these patients, to a certain extent, are overtreated, which could put them at the risk of relatively high surgery-related complications and the sustainable altered quality of life.^23–26 However, the current conventional bladder preserving therapies and clinical trial options for this disease setting are limited.

It is known that bladder urothelial cancer is radiotherapy sensitive, which is a key member in trimodality therapy for MIBC bladder-sparing strategy.^{27 28} A set of published studies have elaborated that radiotherapy could enhance generation of antigen-specific immune responses from many perspectives, including dendritic cell activation, inflammatory tumour-cell death and antigen cross-presentation.²⁹ Radiotherapy is regarded as a trigger of immune response-related system antitumour activity. Several groups have showed improved local and distant control effects when radiotherapy combines with checkpoint blockade immunotherapy in different tumour types.^{29 30} Therefore, immunoradiotherapy maybe a potential bladder preservation treatment for patients with high risk NMIBC. Recently, Zhiyong et al reported tislelizumab combined with radiotherapy as a promising bladder-preserving therapy for patients with BCG-unresponsive high NMIBC who were ineligible for or refused radical cystectomy with DFS rate at 12 months was 80.0% (95% CI, 67.4% to 92.6%), at 24 months DFS was 60.0% (95% CI, 40.3% to 79.7%).³¹ The radiotherapy dose was 60 Gy (60−66) in 30 fractions, and it took nearly 2 months to finish the radiotherapy, which might be a challenge to patient compliance.

The current HOPE-04 is a prospective open-label, single-arm, phase II study, designing to evaluate the safety and efficacy of short-course radiotherapy (5×5 Gy) and toripalimab (PD-1 antibody) as a novel bladder sparing treatment in patients with high-risk/extremely high risk NMIBC. Fifty-five patients with pathological and imaging diagnosed NMIBC with or without BCG treatment will be recruited. Radiotherapy of 5×5 Gy/fractions will be given to the whole bladder and concomitant administration of toripalimab. And a focal tumour bed boost of 9–18 Gy in 3–6 fractions will be given sequentially after the whole bladder radiation. The primary endpoints are DFS and safety. The secondary endpoint is OS. Implementation rate of salvage surgery and quality of life and so on will also be evaluated. Because this is a phase II trial single-arm study conducted in one cancer centre, the patient sample is limited and the results need to be verified in further randomised, multicentre, phase III trial with larger sample size.

With the implementation of the study, HOPE-04 will give a description about the safety profile of short-course radiotherapy and toripalimab combination as a bladder preservation treatment for high-risk/extremely high risk NMIBC. Moreover, the control efficacy of local disease and distant metastasis will be explored as well in this population. Hopefully, with the combination of local therapy and system treatment, the DFS can be prolonged and the probability of early cystectomy can be reduced or suspended. Moreover, the quality of patients’ life can be improved, which provides a promising option for patients with NMIBC with bladder-sparing will. Additionally, the cost of radiotherapy applied in the current study will be reduced, and this immune-radiotherapy combination will extend the therapeutic options from the perspective of cost-effectiveness analysis.

Ethics approval and consent to participate

The treatment protocol was approved by the medical ethics committee of West China Hospital, Sichuan University (Approval number: 2022–1759) Chinese Ethics Committee of Registering Clinical Trials. Signed informed consent is required before an eligible patient is enrolled. Additionally, the study was performed in accordance with the ethical standards put forth in the 1964 Declaration of Helsinki.

We would like to thank Shanghai Junshi Biomedical Technology Co. Ltd. for providing clinical trial subjects toripalimab free of charge.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).

Footnote

Twitter @weiqiang

Contributors YS, PZ, HZ, QW and FW contributed to the concept and design of the study. FW and TL were involved in the organisation of the trial and drafting the manuscript. All authors have given final approval of the version of the protocol.

Funding National Natural Science Foundation of China, Grant/Award Number: 81802445; Science & Technology Department of Sichuan Province, Grant/Award Number: 2022NSFSC1564.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

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