BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas.

BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).

Renal cell cancer: a shift in approaches for treatment of advanced disease in the United States.

Several new agents have become available to treat renal cell cancer (RCC) in recent years, although evidence on their dissemination is limited. This study examined recent trends in RCC treatment in US community practices. Data from the population-based National Cancer Institute's Patterns of Care studies were used to evaluate treatment of patients with RCC newly diagnosed in 2004 and 2009 (N=2357). Descriptive statistics and logistic and Cox proportional hazards regression analyses were used to assess treatment patterns and the associations among demographic, clinical, and hospital characteristics, with receipt of systemic therapy and time-to-systemic treatment. Between 2004 and 2009, systemic therapy use increased among patients with stage III and IV RCC, from 3.8% to 15.7% and 35.2% to 57.4%, respectively. Among patients with stage IV disease, the most commonly used therapies changed from interleukin-2 (16.3%) and interferon-alfa (16.6%) in 2004 to sunitinib (39.2%) and temsirolimus (15.2%) in 2009. Further, notable decreases were seen in the use of surgery and time-to-systemic treatment for patients with stage IV disease. Patients who were older, living in areas with lower educational attainment, and diagnosed in 2004 were significantly less likely to receive systemic therapy and had longer time-to-systemic treatment (P<.05). The findings indicate that over the past decade, treatment for RCC in the United States has evolved toward increased use of systemic therapy. As the diffusion of new therapies continues, it will be imperative to understand how variation in care for RCC will impact health outcomes and costs of care.

Total knee arthroplasty after high tibial osteotomy: a registry-based case-control study of 1,036 knees.

INTRODUCTION: Total knee arthroplasty (TKA) after high tibial osteotomy (HTO) is a technically demanding procedure, and concerns have been raised that previous HTO might compromise the outcome of TKA. The aims of the study were to assess the survivorship of TKA after HTO and to determine whether the survivorship is similar to that of primary TKA without previous HTO. MATERIALS AND METHODS: Using the Finnish Arthroplasty Register and the National Hospital Discharge Register, we extracted the data of 1,036 patients [mean age 64.3 years; followup 6.7 years (0-22)] who had undergone TKA after a previous HTO between 1987 and 2008. From this cohort, we calculated the Kaplan-Meier survivorship and compared the survivorship of these cases to that of 4,143 age- and gender-matched patients who had undergone primary TKAs without previous HTO. RESULTS: In the TKA after HTO group, we found Kaplan-Meier survivorship to be 95.3% at 5 years, 91.8% at 10 years, and 88.4% at 15 years. Those survivorship values were lower than those of patients who had TKA without previous HTO (97.2, 94.5, and 90.6%, respectively) (hazard ratio 1.40; 95% confidence interval 1.09-1.81; p = 0.010). CONCLUSIONS: Previous studies have described technical difficulties during the TKA procedure after HTO, but they have found no adverse effects on the outcome. Our study supports previous research, and despite the slightly higher revision rate, TKA after HTO provides satisfactory results when compared to routine primary TKAs.

Assessing non-cancer-related health status of US cancer patients: other-cause survival and comorbidity prevalence.

With advances in prevention, screening, and treatment, cancer patients are living longer; hence, non-cancer-related health status will likely play a larger role in determining their life expectancy. In this study, we present a novel method for characterizing non-cancer--related health status of cancer patients using population-based cancer registry data. We assessed non-cancer-related health status in the context of survival from other causes of death and prevalence of comorbidities. Data from the Surveillance, Epidemiology, and End Results program (2000-2006) were used to analyze cancer patients' survival probabilities by cause of death. Other-cause survival was estimated using a left-truncated survival method with the hazard of death due to other causes characterized as a function of age. Surveillance, Epidemiology, and End Results data linked to Medicare claims (1992-2005) were used to quantify comorbidity prevalence. Relative to the US population, survival from a non-cancer-related death was higher for patients diagnosed with early stage breast and prostate cancer but lower for lung cancer patients at all stages. Lung cancer patients had worse comorbidity status than did other cancer patients. The present study represents the first attempt to evaluate the non-cancer-related health status of US cancer patients by cancer site (breast, prostate, colorectal, and lung) and stage. The findings provide insight into non-cancer-related health issues among cancer patients and their risk of dying from other causes.

Phase 2 trial design in neuro-oncology revisited: a report from the RANO group.

Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents--which are competing for a small patient population, in view of the low incidence of primary brain tumours--draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs--such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs--can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology.

SAPHO syndrome presenting as widespread bony metastatic disease of unknown origin.

SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome represents an inflammatory spectrum ranging from an osteitis through to a spondyloarthropathy which may or may not be associated with dermatological manifestations. We present the case of a 52-year-old female who presented with non-specific back pain. Radiological imaging showed mixed lytic and sclerotic lesions of her lumbar spine and pelvis consistent with bony metastatic disease. She underwent CT-guided biopsy that confirmed histological findings in keeping with non-bacterial osteitis/chronic recurrent multifocal osteomyelitis. This case report and review of the literature highlights the importance of the SAPHO syndrome and its treatment.

Mortality as an indicator of patient safety in orthopaedics: lessons from qualitative analysis of a database of medical errors.

BACKGROUND: Orthopaedic surgery is a high-risk specialty in which errors will undoubtedly occur. Patient safety incidents can yield valuable information to generate solutions and prevent future cases of avoidable harm. The aim of this study was to understand the causative factors leading to all unnecessary deaths in orthopaedics and trauma surgery reported to the National Patient Safety Agency (NPSA) over a four-year period (2005-2009), using a qualitative approach. METHODS: Reports made to the NPSA are categorised and stored in the database as free-text data. A search was undertaken to identify the cases of all-cause mortality in orthopaedic and trauma surgery, and the free-text elements were used for thematic analysis. Descriptive statistics were calculated based on the incidents reported. This included presenting the number of times categories of incidents had the same or similar response. Superordinate and subordinate categories were created. RESULTS: A total of 257 incident reports were analysed. Four main thematic categories emerged. These were: (1) stages of the surgical journey - 118/191 (62%) of deaths occurred in the post-operative phase; (2) causes of patient deaths - 32% were related to severe infections; (3) reported quality of medical interventions - 65% of patients experienced minimal or delayed treatment; (4) skills of healthcare professionals - 44% of deaths had a failure in non-technical skills. CONCLUSIONS: Most complications in orthopaedic surgery can be dealt with adequately, provided they are anticipated and that risk-reduction strategies are instituted. Surgeons take pride in the precision of operative techniques; perhaps it is time to enshrine the multimodal tools available to ensure safer patient care.

A rare patella anatomical abnormality causing locking in an adolescent girl.

UNLABELLED: Locking is an inability to fully extend the knee and is most commonly associated with meniscal pathology and loose bodies. The locked knee is an infrequent presentation in paediatric orthopaedics, and the presence of a patella protuberance as a cause has never been reported in children or adults. An adolescent female presented with a 4-year history of intermittent locking of the right knee associated with a painful audible 'clunk' on full extension. Plain film radiographs and computed tomography showed a posteriorly projecting bony protuberance over the inferior aspect of the patella. The protuberance was removed via an arthrotomy, and the patient made significant improvement in pain and function with no further locking episodes experienced. LEVEL OF EVIDENCE: IV.

Nitrofurantoin-induced lung disease and prophylaxis of urinary tract infections.

Nitrofurantoin is commonly used for the treatment and prophylaxis of recurrent urinary tract infections (UTIs). Although relatively rare, nitrofurantoin is one of the commonest causes of drug-induced pulmonary disease, which can be potentially serious and even fatal. Knowledge of such potential adverse effects is essential to enable early recognition and withdrawal of the drug. Patients on long-term nitrofurantoin should be reviewed and monitored regularly. Management involves early consideration of the condition, and prompt withdrawal of the drug. We report three cases of nitrofurantoin-induced lung disease in patients who were on long-term nitrofurantoin for UTI prophylaxis and present a brief review of the literature on this subject.

Considerations on Integrating Prostate-Specific Membrane Antigen Positron Emission Tomography Imaging Into Clinical Prostate Cancer Trials by National Clinical Trials Network Cooperative Groups.

PURPOSE: As prostate-specific membrane antigen (PSMA) positron emission tomography (PET) becomes increasingly available in the United States, the greater sensitivity of the technology in comparison to conventional imaging poses challenges for clinical trials. The NCI Clinical Imaging Steering Committee (CISC) PSMA PET Working Group was convened to coordinate the identification of these challenges in various clinical scenarios and to develop consensus recommendations on how best to integrate PSMA PET into ongoing and upcoming National Clinical Trials Network (NCTN) trials. METHODS: NCI CISC and NCI Genitourinary Steering Committee members and leadership nominated clinicians, biostatisticians, patient advocates, and other imaging experts for inclusion in the PSMA PET Working Group. From April to July 2021, the working group met independently and in conjunction with the CISC to frame challenges, including stage migration, response assessment, trial logistics, and statistical challenges, and to discuss proposed solutions. An anonymous, open-ended survey was distributed to members to collect feedback on challenges faced. Representatives from each NCTN group were invited to present an overview of affected trials. From these discussions, the consensus document was developed and circulated for the inclusion of multiple rounds of feedback from both the Working Group and CISC. RESULTS: The current consensus document outlines the key challenges for clinical prostate cancer trials resulting from the increasing availability of PSMA PET. We discuss implications for patient selection and definition of end points and provide guidance and potential solutions for different clinical scenarios, particularly with regard to best practices in defining eligibility criteria and outcome measures. RECOMMENDATIONS: This article provides guidance regarding clinical trial design and conduct, and the interpretation of trial results.

High-grade intra-articular liposarcoma of the knee.

A high-grade pleomorphic intra-articular liposarcoma of the knee is described in a 48-year-old man, which was diagnosed histologically after arthroscopy of the knee for suspected pigmented villonodular synovitis (PVNS). The patient proceeded to undergo an extra-articular resection with a custom-made prosthesis. This report highlights the need to remember this rare tumour in the differential diagnosis of atypical soft tissue lesions within the knee joint prior to instrumentation.

Bilateral symmetrical metachronous myxofibrosarcoma: a case report and review of the literature.

Soft tissue sarcomas (STS) are rare. Affected patients are at increased risk of developing a second primary malignancy, particularly another primary STS. These rarely affect the extremities, tending to occur in the abdomen, head or neck. We describe a patient with myxofibrosarcoma of the buttock who developed a second primary tumour of the same histological type in the contralateral buttock thirty months after excision. Remarkably, the second tumour was symmetrical and there were no predisposing factors or evidence of metastatic spread. The second tumour was a significant size at presentation with encasement of the sciatic nerve. Awareness of the sarcoma patient's increased risk of developing a second tumour could lead to earlier diagnosis and improved outcome. A review of the literature on multiple soft tissue sarcomas is also presented.

Avulsion fracture of the anterior superior iliac spine: misdiagnosis of a bone tumour.

Avulsion fractures of the anterior superior iliac spine are rare. This injury is usually seen in adolescents, as an avulsion fracture of the apophyses, a result of sudden vigorous contraction or repetitive contraction of the sartorius and tensor fasciae latae muscles. Treatment for this injury is usually conservative; however, surgical management has been reported in those with significant displacement. We present a 14 year old male patient who was referred to our unit for biopsy of a possible pathological fracture of his right ilium. The authors feel it is essential to understand the importance of ruling out a bone tumour, if the possibility has been raised, before managing a suspected fracture. If there is any doubt, the case should be referred to an appropriate sarcoma unit for review prior to any intervention.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.

Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy.

BACKGROUND: Neutrophils are increased in the airways and in induced sputum of severe asthma patients. We determined the expression of activation markers from circulating neutrophils in severe asthma, and their supressibility by corticosteroids. METHODS: We compared blood neutrophils from mild, moderate-to-severe and severe steroid-dependent asthma, and non-asthmatics (n = 10 each). We examined the effect of adding or increasing oral prednisolone (30 mg/day;1 week). RESULTS: Flow cytometric expression of CD35 and CD11b, but not of CD62L or CD18, was increased in severe asthma. F-met-leu-phe increased CD11b, CD35 and CD18 and decreased CD62L expression in all groups, with a greater CD35 increase in severe asthma. In severe steroid-dependent asthma, an increase in prednisolone dose had no effect on neutrophil markers particularly CD62L, but reduced CD11b and CD62L on eosinophils. Phorbol myristate acetate-stimulated oxidative burst and IL-8 release by IL-1beta, lipopolysaccharide and GM-CSF in whole blood from mild but not severe asthmatics were inhibited after prednisolone. There were no differences in myeloperoxidase or neutrophil elastase release from purified neutrophils. CONCLUSION: Because blood neutrophils in severe asthma are activated and are not inhibited by oral corticosteroids, they may be important in the pathogenesis of severe asthma.

Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.

PURPOSE: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. EXPERIMENTAL DESIGN: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. RESULTS: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. CONCLUSIONS: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.

Toward greater adoption of minimally invasive and nephron-sparing surgical techniques for renal cell cancer in the United States.

PURPOSE: To examine national, population-based utilization trends of nephron-sparing and minimally invasive techniques for the surgical management of patients with adult renal cell cancer (RCC) in the United States. METHODS: Linked data from the National Cancer Institute׳s Patterns of Care studies and the Area Health Resource File were used to evaluate trends of nephron-sparing and minimally invasive techniques in a sample of 1,110 patients newly diagnosed with American Joint Committee on Cancer stages I-II RCC, in 2004 and 2009, who underwent surgery. Descriptive statistics were used to assess patterns of surgery between 2004 and 2009. Multivariable logistic regression analyses were used to evaluate the associations between demographic, clinical, hospital, and area-level health care characteristics with surgery utilization, stratified by the subset of patients who were potentially eligible for partial nephrectomy (PN) vs. radical nephrectomy (RN) and laparoscopic RN (LRN) vs. open RN, respectively. RESULTS: Between 2004 and 2009, PN use among stage I patients with tumors≤7cm increased from 29% to 41%, respectively (P = 0.22). Among patients with stage I tumors≤4cm, use of PN significantly increased from 43% in 2004 to 55% in 2009 (P≤0.05). Among patients with stage I tumors>4 to 7cm, laparoscopic partial nephrectomy increased from 8% to 15%, whereas LRN increased from 38% to 69%, between 2004 and 2009 (P = 0.07). Significant increases in LRN use were observed for both stage I (from 43% in 2004 to 58% in 2009; P≤0.05) and stage II patients (from 16% in 2004 to 47% in 2009; P≤0.01). Patients diagnosed at an older age, with larger tumors, non-clear cell RCC and who did not receive treatment in a hospital with residency training were significantly less likely to receive PN vs. RN; whereas, those diagnosed in 2009 with stage I disease were significantly more likely to receive LRN vs. open RN. CONCLUSIONS: This study highlights a significant shift toward increased use of nephron-sparing and minimally invasive surgical techniques to treat patients with RCC in the United States. Our findings are among the first population-based reports in which most eligible patients with RCC received PN over RN. In light of the long-standing evidence on the improved patient outcomes, future investigation is warranted to identify the barriers to increased adoption of these nephron-sparing and minimally invasive approaches.

Summary and Recommendations from the National Cancer Institute's Clinical Trials Planning Meeting on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer.

The NCI Bladder Cancer Task Force convened a Clinical Trials Planning Meeting (CTPM) Workshop focused on Novel Therapeutics for Non-Muscle Invasive Bladder Cancer (NMIBC). Meeting attendees included a broad and multi-disciplinary group of clinical and research stakeholders and included leaders from NCI, FDA, National Clinical Trials Network (NCTN), advocacy and the pharmaceutical and biotech industry. The meeting goals and objectives were to: 1) create a collaborative environment in which the greater bladder research community can pursue future optimally designed novel clinical trials focused on the theme of molecular targeted and immune-based therapies in NMIBC; 2) frame the clinical and translational questions that are of highest priority; and 3) develop two clinical trial designs focusing on immunotherapy and molecular targeted therapy. Despite successful development and implementation of large Phase II and Phase III trials in bladder and upper urinary tract cancers, there are no active and accruing trials in the NMIBC space within the NCTN. Disappointingly, there has been only one new FDA approved drug (Valrubicin) in any bladder cancer disease state since 1998. Although genomic-based data for bladder cancer are increasingly available, translating these discoveries into practice changing treatment is still to come. Recently, major efforts in defining the genomic characteristics of NMIBC have been achieved. Aligned with these data is the growing number of targeted therapy agents approved and/or in development in other organ site cancers and the multiple similarities of bladder cancer with molecular subtypes in these other cancers. Additionally, although bladder cancer is one of the more immunogenic tumors, some tumors have the ability to attenuate or eliminate host immune responses. Two trial concepts emerged from the meeting including a window of opportunity trial (Phase 0) testing an FGFR3 inhibitor and a second multi-arm multi-stage trial testing combinations of BCG or radiotherapy and immunomodulatory agents in patients who recur after induction BCG (BCG failure).