BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets
Abstract
:1. Introduction
2. Intravesical Chemotherapy
3. Chemo-Hyperthermia
4. Immunotherapy and Inflammation-Targeted Agents
5. Gene Therapy
6. Other Therapies
7. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author, Year | Patients Number | Study Design | Treatment | Regimen | Effects of Treatment | Main Findings |
---|---|---|---|---|---|---|
Chevuru et al., 2023 [25] | 97 | Retrospective | Gemcitabine Docetaxel | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis Docetaxel: inhibition of cell division | 12, 24, and 60 months RFS 57%, 44%, and 24% (12, 24, and 60 months HG-RFS 60%, 50%, and 30%, respectively); BCG unresponsive: 12, 24, and 60 months RFS 67%, 50%, and 28%; CIS-only: 1-, 2-, and 5-year RFS 48%, 38%, and 22%, papillary only: 1-, 2-, and 5-year RFS 64%, 49%, and 25% (p = 0.3); 12, 24, and 60 months RC-free survival 89%, 86%, and 75% |
Hurle et al., 2020 [26] | 36 | Open-label, single-arm | Gemcitabine | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis | 12 and 24 months DFS 44.44% (95% CI 28.02–59.64%) and 31.66% (95% CI 16.97–47.43%); 12 and 24 months PFS 80.13% (95% CI: 62.78–90.00%) and 69.55% (95% CI: 50.33% 82.52%), 24 months CSS 80.68% (95% CI 61.49–90.96%), 24 months OS 77.9% (95% CI 58.78–88.92%) |
Steinberg et al., 2020 [27] | 276 | Retrospective | Gemcitabine Docetaxel | Induction +/− maintenance | Gemcitabine: inhibition DNA synthesis Docetaxel: inhibition of cell division | 1 and 2 years RFS 60% and 46% (43% if CIS present); HG 1 and 2 years RFS 65% and 52% (50% if CIS present) |
DeCastro et al., 2020 [28] | 18 | Phase I trial | Cabazitaxel Gemcitabin Cisplatin | Induction +/− maintenance (cabazitaxel + gemcitabine) | Cabazitaxel: inhibition of cell division Gemcitabine: inhibition of DNA synthesis Cisplatin: inhibition of DNA replication and transcription | CR rate: 89%; PR: 94% (negative biopsy but positive cytology). One and two years RFS 0.83 (range 0.57 to 0.94) and 0.64 (0.32 to 0.84), median 27 months. One- and two-years RC-free survival 0.94 (0.67 to 0.99) and 0.81 (0.52 to 0.94) |
Milbar et al., 2017 [29] | 33 (22 BCG unresponsive/relapsing) | Retrospective | Gemcitabine Docetaxel | Induction +/− maintenance | Gemcitabine: inhibition DNA synthesis Docetaxel: inhibition of cell division | 1 and 2 years DFS38% and 24%. One and two years HG-RFS 49% and 34%. |
Dalbagni et al., 2017 [30] | 19 | Single-arm, phase I/II trial | Gemcitabine Everolimus (oral) | Gemcitabine induction + everolimus maintenance | Gemcitabine: inhibition of DNA synthesis Everolimus: mTOR inhibition | 3, 6, and 9, 12 months RFS 58% (95% CI 33–76%), 27% (95% CI 9–49%) and 20% (95% CI 5–42%) |
Robins et al., 2017 [31] | 22 | Single-arm, open-label, phase II trial | Nab-paclitaxel | Induction +/− maintenance | Nab-paclitaxel: inhibition of cell division | Overall CR 36%, non-CIS CR 63, CIS CR 25%. One and three-year RFS 32% and 18% (no CIS CR 40%, CIS CR 10%), |
Cockerill et al., 2016 [32] | 27 | Retrospective | Gemcitabine MMC | Induction, no standardized maintenance | Gemcitabine: inhibition of DNA synthesis MMC: inhibition of DNA functions. | 63% recurrence rate, median RFS 15.2 months (range 1.7–32). RFS 37% (median follow-up 22 months) |
Steinberg et al., 2015 [33] | 45 | Retrospective | Gemcitabine Docetaxel | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis Docetaxel: inhibition of cell division | Treatment success (no recurrence + no cystectomy) 66% at 12 weeks, 54% at 1 year, 34% at 2 years; median time to failure 3.1 months (range 2.2–25.9) |
Lightfoot et al., 2014 [34] | 52 (10 BCG naive) | Retrospective | Gemcitabine MMC | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis MMC: inhibition of DNA functions. | CR 68%, 1- and 2-year RFS, 48%, and 38% |
McKiernan et al., 2014 [35] | 28 | Single-arm, phase II trial | Nab-paclitaxel | Induction +/− maintenance | Nab-paclitaxel: inhibition of cell division | 35.7% CR, 1 and 2-year RFS 35.7% and RFS 30.6%. 12, 24, and 36 months CFS 74%, 74%, and 55% |
Barlow et al., 2013 [36] | 54 | Retrospective | Docetaxel | Induction +/− maintenance | Docetaxel: inhibition of cell division | 59% CR (cystoscopy with biopsy + cytology); 1- and 3-year RFS 40% and 25%; 31% RC rate |
Skinner et al., 2013 [37] | 58 | Single-arm, open-label, phase II trial | Gemcitabine | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis | 3 months CR (negative cystoscopy, urinary cytology +/− biopsy) 47%. Median RFS 6.1 months (95% CI 16–43), 21% at 24 months. Progression/RC rate 36%. |
Sternberg et al., 2013 [38] | 69 | Retrospective | Gemcitabine | Induction | Gemcitabine: inhibition of DNA synthesis | 5 years progression rate 19% for BCG-refractory pts, 22% for pts with other types of BCG failure (HR 1.09, 95% CI 0.34–3.50). CR (negative cystoscopy and cytology) in 27 pts, PR (negative cystoscopy and positive cytology in 19 with), NR (positive cystoscopy) 20 pts. Subsequent RC in 20 pts |
Steinberg et al., 2011 [39] | 90 | Single-arm, pivotal phase III open-label study | Valrubicin | Induction | Valrubicin: inhibition of DNA and RNA synthesis | CR in 18 pts at 3 and 6 months (negative cytology, cystoscopy, and biopsy), NR 64 pts |
McKiernan et al., 2011 [40] | 18 | Phase I trial | Nab-paclitaxel | Induction | Nab-paclitaxel: inhibition of cell division | CR in 5 patients (28%), 13 NR (stage progression in 1) |
Bassi et al., 2011 [41] | 16 | Single-arm, open-label, phase I trial | Paclitaxel-hyaluronic acid | Induction | Paclitaxel: inhibition of cell division | 6 NR (40%), 9 disease-free pts (60%) |
Di Lorenzo et al., 2010 [42] | 80 | Multicentric, phase II trial, randomized | Gemcitabine vs. BCG | Induction + maintenance for both arms | Gemcitabine: inhibition of DNA synthesis BCG: stimulating cellular and humoral immune response | 2-year RFS 19% for Gem (95% CI, 5–39), 3% for BCG (95% CI, 0–21; HR, 0.15; 95% CI, 0.1–0.3.008). Progression rate 33% for Gem, 37.5% for BCG |
Perdonà et al., 2010 [43] | 20 | Single-arm, phase II trial | Gemcitabine | Induction + maintenance | Gemcitabine: inhibition of DNA synthesis | 3 months CR at the first 75%; 55% recurrence rate (11 of 20 pts); 45% progression rate (5 of 11 pts) |
Laudano et al., 2010 [44] | 18 | Single-arm, phase I trial | Docetaxel | Induction | Docetaxel: inhibition of cell division | 22% CR, 17% PR (NMIBC recurrence requiring TURBT with no further treatment), 61% NR (RC or further pharmacologic therapy). PFS 89%. |
Addeo et al., 2010 [45] | 109 | Phase III trial randomized | Gemcitabine vs. MMC | Induction +/− maintenance for both arms | Gemcitabine: inhibition of DNA synthesis MMC: inhibition of DNA functions. | RFS in gemcitabine arm, 72% (39 of 54 pts), in MMC arm 61% (33 of 55 pts). Stage progression in 10 pts in the MMC arm and 6 in the gem arm |
Ignatoff et al., 2009 [46] | 38 | Multicentric, single-arm, phase II trial | AD32 (doxorubicin analog with limited systemic exposure) | Induction | AD32: inhibition of DNA functions and induction of apoptosis | CR 42.9% (90% CI: 24.5%, 62.8%), CIS CR 23.8% (90% CI: 9.9%, 43.7%). 12 and 24 RFS months 20% (90% CI: 7.8–36.1%) and 15% (CI, 4.9%, 30.2%),12 and 24 CIS RFS 80% (90% CI, 31.4%, 95.8%) if previous CR. PFS 22.4 months, CIS PFS 8.7 months |
Mohanty et al., 2008 [47] | 35 | Single-arm, non-randomized, phase I trial | Gemcitabine | Induction | Gemcitabine: inhibition of DNA synthesis | At 18 months follow-up 21 disease free pts (60%), 11 pts (31.4%) with superficial recurrences, 3 (8.75%) with MIBC. Average RFS 12 months, average time to progression 16 months. |
Gunelli et al., 2007 [48] | 40 | Single-arm, phase II trial | Gemcitabine | Induction | Gemcitabine: inhibition of DNA synthesis | 95% (38 of 40 pts) CR at 6 months (cystoscopy + cytology); overall event-free survival rate 80% at 1 year and 66% at 2.5 years. At a median follow-up of 28 months, 35% relapse rate (NMIBC). RC in 2 pts |
Dalbagni et al., 2006 [49] | 30 | Single-arm, phase II trial | Gemcitabine | Induction | Gemcitabine: inhibition of DNA synthesis | 50% CR; median RFS 3.6 months (95% CI, 2.9 to 11.0 months); 21% 1-year RFS in pevious CR (95% CI, 0% to 43%). RC rate 37% |
McKiernan et al., 2006 [50] | 18 | Single-arm, phase I trial | Docetaxel | Induction | Docetaxel: inhibition of cell division | CR in 56% (10 pts) |
Bartoletti et al., 2005 [51] | 40 BCG refractory (total population 116) | Multicentric, single-arm, phase II trial | Gemcitabine | Induction | Gemcitabine: inhibition of DNA synthesis | Recurrence rate 32.5%, relapse in 6 (25%) of 24 intermediate-risk BCG refractory pts and 7 (43.7%) of 16 BCG refractory high-risk pts |
Bassi et al., 2005 [52] | 9 | Single-arm, phase I trial | Gemcitabine | Induction +/− maintenance | Gemcitabine: inhibition of DNA synthesis | CR in 4/9 pts |
Dalbagni et al., 2002 [53] | 14 | Single-arm, phase I trial | Gemcitabine | Induction (dose levels 500 mg, 1.000 mg, 1.500 mg, and 2.000 mg. | Gemcitabine: inhibition DNA synthesis | CR (defined as a negative posttreatment cystoscopy with biopsy of the urothelium + negative cytology) in 7, failure in 11 (negative bladder biopsy + persistent positive cytology), RC rate 1/11 pts |
Author, Year | Patients Number | Study Design | Treatment | Regimen | Effects of Treatment | Main Findings |
---|---|---|---|---|---|---|
Marquette et al., 2020 [59] | 22 | Retrospective | HIVEC MMC | Induction | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | Progression to MIBC: 2 pts (9.1%) Time to to RC: 4 pts (18.2%) |
De Jong et al., 2018 [60] | 55 | Post hoc analysis of prospective data | MMC + hyperthermia | Induction + maintenance | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | Median DFS 17.7 months, papillary only DFS 28.8 months, papillary + CIS DFS 17.7 months, T1/ T1 + CIS DFS 12.1 months CR 70% at 3 months if concomitant CIS. One-year disease recurrence/progression 53%. Overall CR 50%, recurrence rate 42% and progression rate 8%. RC rate 50% |
Tan et al., 2019 [61] | 104 (48 randomized to MMC + hyperthermia) | Phase III trial, open-label, randomized with control | MMC + hyperthermia vs. BCG or institutional standard of care defined at randomization | Induction +/− maintenance | MMC: Inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. BCG: stimulating cellular and humoral immune response. | No statistically significant differences between the 2 arms in 24 months DFS (35% vs. 41%, HR 1.33, 95% CI 0.84–2.10, p = 0.23; adjusted p = 0.49) and 3 months CIS CR (30% vs. 47%, OR 0.43, 95% CI 0.18–1.28, p = 0.15). Lower DFS of experimental arm lower if CIS (HR 2.06, 95% CI 1.17–3.62, p = 0.01). 24 months DFS in non-CIS pts for experimental and control arms 53% and 24%,. worse DFS in papillary tumor + CIS than in CIS only. No differential treatment effect in CIS only pts (HR 1.53, 95% CI 0.77–3.05, p = 0.22). No difference between the arms in PFS (24 month rates 83% vs. 87%, p = 0.16), and RFS (24 month rates 23% vs. 40%; p = 0.98), borderline difference in DSS (24 month rates 89% vs. 96%; p = 0.04). Progression in 4 pts in both arms. |
Soria et al., 2016 [62] | 34 | Multicentric, single-arm, phase I–II trial | MMC + hyperthermia | Induction | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | Response rate 59%, 42 NR, 1-year progression rate 18%; 41 months DFS 44.1%. RFS 10.5 months, PFS 29.5 months, RC-free survival 20 months (range 8–60). At median follow-up of 41 months, recurrence and progression rates 35.3 and 23.5% |
Inman et al., 2014 [63] | 15 | Pilot prospective trial | MMC + hyperthermia | Induction +/− maintenance | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | 67% recurrence rate, RFS 15.4 months, 60% RC rate, RC-free survival 20.1 months |
Witjes et al., 2009 [64] | 51 (17 BCG refractory, 15 BCG relapsing) | Retrospective | MMC + hyperthermia | Induction + maintenance | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | CR (negative cytology and biopsy) 92%, 50% at 2 years. 49% recurrence rate, mean RFS 27 months (median 22 months). |
Nativ et al., 2009 [65] | 111 | Retrospective | MMC + hyperthermia | Induction + maintenance | MMC: inhibition of DNA functions. Hyperthermia: DNA damage, ROS generation, cell death induction, damage to tumor vascular system, activation of immune response. | 1 and 2 year DFS 85% and 56%, respectively; average DFS 16 months; 3% progression rate to MIBC. Two-year recurrence rate of 61% if maintenance not administered, 39% if administered. |
Author, Year | Patients Number | Study Design | Treatment | Regimen | Effects of Treatment | Main Findings |
---|---|---|---|---|---|---|
Meghani et al., 2022 [69] | 9 | Single-arm, phase I trial | BCG + pembrolizumab (intravesical) | Induction + maintenance (pembrolizumab only) | BCG: stimulating cellular and humoral immune response. Pembrolizumab: stimulation of immune response. | 3, 6, and 12 months RFS 100%, 67% (95% CI: 42–100%) and 22% (95% CI: 7–75%), respectively. Median RFS 6.2 months. Progression in 5 pts, 6 and 12 months PFS 100% and 56% (95% CI: 31–100%) |
Chamie et al., 2022 [68] | 171 (cohorts A and C: pts with BCG-unresponsive CIS with or without Ta/T1 papillary NMIBC; cohort B pts with BCG-unresponsive high-grade Ta/T1 papillary NMIBC) | Pivotal trial, multicentric open-label, single-arm, three- cohort | IL-15 superagonist NAI (intravesical) + BCG vs. NAI (intravesical) alone | Induction +/− maintenance | NAI: stimulation of immune response. BCG: stimulating cellular and humoral immune response. | Cohort A: 71% 3, 6, and 12 months CR 55% (45 of 82 patients; 95% CI = 43.5% to 65.9%), 56% (46 of 82 patients; 95% CI = 44.7% to 67.0%), and 45% (37 of 82 patients; 95% CI = 34.1% to 56.5%). 24 months PFS 84.7%%. 7% RC rate in CR pts, 33% in NR Cohort B: 12, 18 and 24 months DFS 55.4% (95% CI = 42.0% to 66.8%), 51.1% (95% CI = 37.6% to 63.1%) and 48.3% (95% CI = 34.5% to 60.7%). RC rate 7%. Cohort C: 3 months CR 20%, 10% of pts with CR maintained at 6 months |
Alanee et al., 2021 [67] | 18 | Single-arm, phase I trial | BCG + intravenous pembrolizumab | BCG induction + 6 doses of pembrolizumab every 3 weeks concurrently with BCG | BCG: stimulating cellular and humoral immune response Pembrolizumab: stimulation of immune response. | CR 69% at 3 months following BCG treatment. One patient progressed to MIBC. |
Balar et al., 2021 [10] | 96 | Open-label, single-arm, multicentric, phase II trial | Pembrolizumab (intravenous) | Every 3 weeks up to 24 months | Pembrolizumab: stimulation of immune response. | 39 pts (41%; 95% CI 30∙7–51∙1) achieved CR at 3 months, median duration of CR 16.2 months (95% CI 6∙7–36∙2), 51% recurrence after CR. At 12 months PFS to worsening of grade or stage or death 83% (95% CI 70.22–90.4), PFS to MIBC or metastatic disease or death 97% (86.0–99.2). |
Li et al., 2017 [70] | 94 | Retrospective | MCNA | Induction +/− maintenance | MCNA: stimulation of immune response, apoptosis induction. | 6, 12, and 24 months DFS 48.9% (95% CI 38.0–59.0%), 34.8% (95% CI 24.7–45%) and 28.3% (15.7–34.3%). Papillary-only 6, 12, and 24 months DFS 61.2% (95% CI 38.2–77.8%), 61.2% (95% CI 38.2–77.8%) and 50.1% (95% CI 27.5–69.0%) at 2 years. In pts with CIS +/− papillary disease 6, 12 and 24 months DFS 44.8% (95% CI 32.3–56.4%), 26.5% (95% CI 16.3–37.9%) and 16.6% (95% CI 8.6–26.9%). 47.9% RC rate, 16% progression rate to MIBC and 11.7% to metastatic disease. |
Huang et al., 2017 [71] | 1 | Case report | ALT-803 (NAI) + BCG | Induction | ALT-803 (NAI): stimulating immune response. BCG: stimulating cellular and humoral immune response. | No evidence of recurrence at 19 months after treatment. |
Morales et al., 2015 [72] | 129 | Open-label multicentric, single-arm phase II trial | MCNA | Induction +/− maintenance | MCNA: stimulation of immune response, apoptosis induction. | 6, 12, and 24 months CR 34.1%, 22.5% and 14.7% at (34%, 195%, and 11% in CIS pts). 21.7% progression rate, 6, 12, 24, and 36 months PFS 95%, 87.3%, 79.8%, and 77.7%. RC rate 43%. |
Kowalski et al., 2012 [73] | 46 | Open-label, multicentric, 2-arm phase I trial | Oportuzumab monatox | Induction +/− maintenance | Oportuzumab monatox: apoptosis induction | CR 44%, 16% at 1 year. One-year recurrence rate 65%. Two pts progressed to MIBC. |
Morales et al., 2009 [74] | 55 | Single-arm, phase II trial | MCNA | Induction +/− maintenance | MCNA: stimulation of immune response, apoptosis induction. | CR 27.3% at 12 and 26 weeks, 31.8% and 22.7% at 12 and 18 months in the group receiving 4 mg, 46.4% at 12 and 26 weeks, 25% and 28.6% at 12 and 18 months in the group receiving 8 mg. |
Joudi et al., 2006 [75] | 1106 (467 BCG failure) | Multicentric, single-arm, phase II trial | BCG + IFNα2b (intravesical) | Induction +/− maintenance | BCG: stimulating cellular and humoral immune response. Interferon alpha-2b: induction of cytotoxic effects | 24 months disease-free rate 45% |
O’Donnel et al., 2004 [76] | 490 (231 BCG failure) | Phase II trial | BCG + IFNα2b (intravesical) | Induction + maintenance | BCG: stimulating cellular and humoral immune response. Interferon alpha 2 b: induction of cytotoxic effects | In BCG failure group, recurrence rate 51.5%, 20.8% at 3 months. 24 months disease-free rate 42%, median RFS 16 months. Progression rate to MIBC 4.3%, to metastatic disease 2.6%. RC rate 3.9% |
Lam et al., 2003 [77] | 32 (20 BCG failure) | Retrospective | BCG + IFNα2b (intravesical) | Induction +/− maintenance | BCG: stimulating cellular and humoral immune response Interferon alpha 2 b: induction of cytotoxic effects. | In BCG failure group, 60% disease-free rate, 40% 3-month failure rate. Three pts underwent RC. |
O’Donnell et al., 2001 [78] | 40 | Multicentric phase II trial | BCG + IFNα2b (intravesical) | Induction + maintenance | BCG: stimulating cellular and humoral immune response Interferon alpha-2b: induction of cytotoxic effects | 12, 24, and 30 months RFS 63%, 53%, and 55% |
Sarosdy et al., 1998 [79] | 86 (60 BCG-resistant CIS, 26 with BCG-intolerant CIS) | Single-arm, phase II trial | Bropirimine | Oral self-administration, 3.0 g/day for 3 consecutive days, weekly, up to 1 year | Bropirimine: stimulation of immune response | CR in 14 pts (30%, 95% CI 16.7 to 42.9) of 47 evaluable BCG-resistant pts, 2 additional pts free of CIS (negative biopsy and negative cytology) but recurrent papillary tumor. Overall CR in 21 pts (24%). RFS in CR pts 65–810 days. RC in 26 pts. Progression to MIBC or metastatic disease in 4 pts (6%). |
Author, Year | Patients Number | Study Design | Treatment | Regimen | Effects of Treatment | Main Findings |
---|---|---|---|---|---|---|
Boorjian et al., 2021 [94] | 151 | Multicentric open-label repeat-dose phase III trial | rAd-IFNa/Syn3 (intravesical) | Induction +/− maintenance | rAd–IFNa2b/Syn3: cytotoxic effects | 3-month CR: 55 (53.4%) CIS pts (with or without a high-grade Ta or T1 tumor). 12-month maintained CR among 25/55 (45.5%). |
Shore et al., 2017 [95] | 40 | Phase II trial, randomized, | rAd–IFNα-2b/Syn3 (intravesical) | Induction +/− maintenance | rAd–IFNa2b/Syn3: cytotoxic effects | 12-month RFS: 35% Time to HG recurrence: 6.5 months. RC rate: 35%. 11 pts were disease-free for 15 to more than 36 months. |
Packiam et al., 2018 [96] | 45 | Open-label, multicentric, single-arm, interventional phase II trial | CG0070 (replication selective serotype-5 oncolytic adenovirus) | Induction +/− maintenance | CG0070: stimulation of immune response for Rb-defective tumor cells | Overall CR: 47% (95% CI: 32–62) CR in CIS: 58% (95% CI: 37–78) CR in CIS ± Ta/T1: 50% (95% CI: 33–67) CR CIS + Ta/T1: 33% (95% CI: 10–65) CR in pure Ta/T1: 33% (95% CI: 8–70) 4 pts developed MIBC over 12-month follow-up 3 cancer-specific deaths |
Navai et al., 2016 [97] | 7 | Single-arm, phase Ib trial | rAd–IFNα-2b/Syn3 (intravesical) | Two administrations +/− second treatment | rAd–IFNa2b/Syn3: cytotoxic effects in selected bladder mucosa cells. | CR in 2 pts (29%). Thereafter, RC in 6 pts (1 was lost to follow-up), and 1 pts died of the disease. |
Dinney et al., 2013 [98] | 17 | Open-label, dose-escalating, non-randomized, multicentric phase I trial | rAd–IFNα-2b/Syn3 (intravesical) | Single treatment (3 patients received a second dose) | rAd–IFNa2b/Syn3: cytotoxic effects in selected bladder mucosa cells. | CR in 7 patients at 3 months, RFS up to 39.2 months. RC performed in 10 pts. |
Burke et al., 2012 [99] | 35 | Single-arm, observational, phase I trial | CG0070 (replication selective serotype-5 oncolytic adenovirus) | Induction +/− maintenance | CG0070: stimulation of immune response for Rb-defective tumor cells | Overall RR: 48.6% CR duration: 10.4 months in responders (with some responses ongoing at 17.0 months) CR 50.0% in pts with CIS only CR in pts with CIS alone or CIS + Ta or T1 tumors: 41.2% Higher CR (58.3%) in Rp-positive pts |
Sidi et al., 2008 [100] | 18 | Single-arm, phase I/II trial | BC-819 DNA plasmid (intravesical) | Induction +/− maintenance | BC-8129 DNA plasmid: inhibition of protein synthesis and induction of cell death. | Overall CR: 22% 35 weeks DFS: 4 pts 49 weeks DFS: 1 pt |
Author, Year | Patients Number | Study Design | Treatment | Regimen | Effects of Treatment | Main Findings |
---|---|---|---|---|---|---|
Kulkarni et al., 2022 [106] | 6 | Single-arm, phase Ib trial | PDT: green light laser (wavelength 520 nm) + intravesical TLD–1433 (ruthenium-based photosensitizer) | Single treatment | Oxygen-reactive species production: cell death induction. | Disease persistence in 3 pts treated with 0.35 mg/cm2 TLD–1433 dose, CR at 3 and 6 months in 2 pts treated with 0.70 mg/cm2 (DFS 18 months), metastatic progression in 1 case |
Zahoor et al., 2018 [108] | 19 | Single-arm, phase II trial | Sunitinib | 12 weeks therapy | Multi-targeted receptor tyrosine kinase (RTK) inhibition: inhibition of cell growth. | DFS 44% at 12 weeks, 50% progression rate, one recurrence. At 12 months 4 pts remained disease free, overall 78% progression rate, median time to progression 4.7 months |
Hahn et al., 2017 [109] | 13 | Single-arm, phase II trial | Dovitinib | 4 weeks therapy cycles (median 4 cycles, range 1–19) | Multi-targeted receptor tyrosine kinase (RTK) inhibition: inhibition of cell growth. | CR in 1 case out of 3 pts with FGFR3 mutation (33%), no response in 11 pts (85%), and progression to MIBC in 1 case (8%). DFS in the CR patient 19 months. RC rate 62% (11 pts) |
Lee et al., 2013 [107] | 34 (BCG refractory + intolerant) | Retrospective | PDT: semiconductor laser (power 3 W, wavelength 662 ± 2 nm) + intravenous Radachlorin | Single treatment | Caspase-3 activation and induction of cell death. | 12, 24, and 30 months DFS 90.9%, 64.4%, and 60.1%, respectively. RC performed in 2 pts |
Berger et al., 2003 [110] | 31 (10 with previous BCG treatment) | Retrospective | PDT: laser (maximal power 7 W, wavelength of 633 nm—red light) + intravesical 5ALA | 1 to 6 treatment sessions | Mitochondrial cytochrome C translocation and induction of cell apoptosis. | 40% RFS at 11.8 months (range 1–26), 60% recurrence rate after a mean follow-up of 12.7 months. Three patients receiving repeated treatment (3 sessions) were disease free at 6.3 months (range 1–11) |
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Claps, F.; Pavan, N.; Ongaro, L.; Tierno, D.; Grassi, G.; Trombetta, C.; Tulone, G.; Simonato, A.; Bartoletti, R.; Mertens, L.S.; et al. BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets. Int. J. Mol. Sci. 2023, 24, 12596. https://doi.org/10.3390/ijms241612596
Claps F, Pavan N, Ongaro L, Tierno D, Grassi G, Trombetta C, Tulone G, Simonato A, Bartoletti R, Mertens LS, et al. BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets. International Journal of Molecular Sciences. 2023; 24(16):12596. https://doi.org/10.3390/ijms241612596
Chicago/Turabian StyleClaps, Francesco, Nicola Pavan, Luca Ongaro, Domenico Tierno, Gabriele Grassi, Carlo Trombetta, Gabriele Tulone, Alchiede Simonato, Riccardo Bartoletti, Laura S. Mertens, and et al. 2023. "BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer: Current Treatment Landscape and Novel Emerging Molecular Targets" International Journal of Molecular Sciences 24, no. 16: 12596. https://doi.org/10.3390/ijms241612596