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BCG has been used in the treatment ofNMIBC for more than 40 years. Nevertheless, its exactworking mechanisms have not been completely discovered.Clinical and basic research done over all theseyears has generated much information but it couldbe summarized in a few simple statements. It has beendemonstrated the best route of administration is intravesical,BCG is superior than intracavitary chemotherapyto prevent recurrence but its adverse events are worse.Recently, it has been demonstrated that BCG could delayor prevent progression to infiltrative cancer. Nevertheless,to achieve this, maintenance therapy is necessary.Therefore, the recommendation is to treat middleand high risk cases with BCG. No significant differencesin efficacy have been found between the variousstrains but differences in recurrence have been foundbetween standard and reduced doses.Furthermore, the presence or absence of side effectsdoes not seem to be a prognostic factor for the efficacyof BCG and, maintenance therapy is not associatedwith a significant increase in toxicity.In the future, the optimal schedule and doses must bedefined, and it probably will be different for each individual.BCG shortage has led to try alternative therapiesthrough chemo hyperthermia or electrical gradientapplication the efficacy of which should be evaluated.New strains and immunological treatments are also underresearch
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Since its introduction in 1976 Bacille Calmette-Guerin (BCG) has become the standard of care inhigh risk non-muscle-invasive bladder cancer (NMIBC).Despite more than 40 years of experience, we do notknow the most optimal BCG dose to maximize effectivenesswhilst minimizing side effects. There is universalagreement that an initial induction course of BCG shouldconsist of 6 weekly instillations if tolerated. However,with regards to the actual dose, data on the comparativeeffectiveness of one third dose versus full dose BCG isinconclusive. Similarly, whilst there is strong evidence supportingthe use of BCG maintenance, this has not beenuniversally adopted. The optimal maintenance regimenis unknown but the minimum length for effective maintenanceBCG therapy seems to be 12 months whilst thereis no evidence to support BCG maintenance beyond36 months.Given the precarious state of worldwide BCG suppliesin the last few years, it is imperative that high qualityrandomized trials are carried out to determine the minimumdose and length of BCG treatment in patients withNMIBC.
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Bladder cancer is the 9th most prevalent cancer in the world. It is divided into muscle invasive bladder cancer (MIBC) and non muscle invasive bladder cancer (NMIBC). Over 75% belong to the second group and it will be classified according to the risk of progression and recurrence. In high and intermediate risk tumors. There is indication for the use of bladder instillations with BCG as it reduces the number of recurrences and disease progression to MIBC. In spite of this, disease control is not possible in all cases and there could be recurrence or progression of the disease to MIBC. This article is a review of the therapeutic options of tumor recurrence after failure of BCG treatment.
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The therapeutic approaches developedaround immune system modulation find the therapeuticcontribution of intravesical Bacillus Calmette Guerin(BCG) for transitional cell bladder cancer anunquestionable example as a proof of concept ofantitumor immunotherapy since more than 30 years ago.Intravesical immunotherapy for urothelial carcinomasis considered with periodic intravesical instillationsschedules, and the one with longer historicdevelopment and wider diffusion is BCG in the formof suspension. BCG is a unique strain obtained fromMycobacterium bovis at the end of the first third of theXX century and represents the historically most successfulimmunotherapeutic modality of all tumors with a highlevel body of evidence.Currently, we even see an unpredictable developmentpotential of this therapeutic modality based onimmunomodulation related with activation or suppressionof T lymphocytes by blocking the immune systemcheckpoints. This option is at this time a decisive stepin the treatment of chemotherapy refractory metastaticurothelial carcinoma. Over the last years, there havebeen advances in the intimate mechanism of action ofintravesical BCG, but there are many open questionsthat will only be answered from complex basic andtranslational research platforms.The objective of this review article is to try to translate thebasic mechanisms currently implicated in the differentphases of antitumor response of BCG in its routine usein clinical practice.Also, to analyze the future lines already active underclinical research with and without implications of themechanisms of action of BCG.We describe the role of interactions basally establishedbetween urothelial tumor cells and cellular and molecularelements of the immune system of the patients withulterior antitumor effector capacity. After intravesica BCG therapy and its interaction, we describe the variousphases of its mechanism of action, namely fixation,internalization and triggering of the lytic cytotoxicantitumor response, and its integration in the currentintravesical treatment regimensThe implication of all these mechanisms in the variedcapacity of clinical response observed in patients,reviewing the current status of knowledge of BCGmechanisms of action, leads unavoidably to the searchof better clinical efficacy through eventual immuneresponse markers and to set the approach to theknowledge of the individual reactivity of the immunesystem of each patient as a determinant factor to beable to adopt adjusted therapeutic patterns
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Mitomycin C is an antitumor alkylating antibiotic agent that inhibits DNA synthesis extensively used as intravesical chemotherapy agent in the adjuvant treatment of urothelial carcinoma.Its clinical efficacy is the context of single early posto-perative instillation was demonstrated by Toley et al. in 1988. Since then, multiple clinical trials and 4 meta-nalyses have endorsed its use with level 1a evidence. The objective of this chapter is to perform a comprehen-sive updated review on the use of MMC in the context of single early instillation at the time of TURBT, the available clinical evidence, most relevant recommendations in the international clinical guidelines, its complications and potential maneuvers for the optimization of its use.
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Urothelial bladder cancer is a very prevalent disease. At the time of diagnosis 70-80% of the cases present as non muscle invasive tumors. These tumors present a high recurrence and progression rates despite intravesical treatment with Bacille Calmette-Guerin and mitomycin C. Moreover, bladder conditions such as its wall impermeability and the fact that intravesical drugs are constantly being diluted by urine and eliminated do not favor the efficacy of intravesical treatment.This review analyzes new intravesical drugs such as gemcitabine or taxanes with promising results as alternative to the usual treatments or after their failure. In the same way, we detail those application vehicles designed to increase the exposition of the drug to the bladder wall and its penetration into it. We emphasize drug releasing systems, albumin nanoparticles, liposomes, magnetic nanocarriers, polymers, thermosensible hydrogels and mucoadhesives such as chitosan.
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Long-term survival for patients withadvanced bladder cancer is precarious, with a 5-yearsurvival of just 5% in metastatic cases.Normally, the binding of PD-L1 to PD-1 alters the immuneactivity by modulating it to inhibit autoimmune diseasesor chronic inflammation. However, some cancers usethis route to block the immune response of the patientand continue growing.The new immunotherapy against bladder cancer aims toblock the ability of tumor cells to resist patient’s immuneresponse by acting on the checkpoints of immune cells.These drugs are able to block the PD-1 receptor presenton the surface of the lymphocytes, or the PD-L1 and PD-L2ligands expressed by the cancer cells; this would preventthe binding of both blocking the immunomodulatorysignal and allowing the T cells continue active againstthe tumor.The therapeutic target of Pembrolizumab and Nivolumabis PD-1, the receptor protein of PD-L1 in immune cells. Therest of molecules approved for different types of cancersuch as Atezolizumab, Avelumab or Durvalumab act onthe PD-L1 protein that is expressed in high concentrationsin some cancer cells.The checkpoint inhibitors offer an effective alternative forpatients for whom previously there were few options fordurable responses, including those who are ineligible forcisplatin-based regimens or who are at risk of significanttoxicity.This review describes the most recent data on agents thatinhibit PD-L1, found on the surface of tumor cells, andPD-1 found on activated T and B cells and macrophages.Research is ongoing to further categorize responses,define ideal patient populations, and investigatecombinations of checkpoint inhibitors to address multiplepathways in the functioning immune system.
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In an effort to decrease recurrence and progression rates in non-muscle-invasive bladder cancer (NMIBC), transurethral resection of a bladder tumor is followed by intravesical instillations using Mitomycin-C (MMC) and Bacillus Calmette-Guérin (BCG). In spite of these adjuvant treatment modalities, recurrence and progression rates remain high. Because of these limitations of current standard therapy and the shortage of BCG, there is a search for alternative forms of treatment in NMIBC. Intravesical MMC combined with hyperthermia, especially RF-induced QHT being most extensively investigated in the past 20 years, is one of these alternatives for intermediate- and high-risk NMIBC. There are several different techniques and devices to create hyperthermia of the bladder wall raising temperatures up to 40.5-44.0 º C. Hyperthermia can be the result of ultrasound waves, direct thermal conduction, or electromagnetic fields. An overview of hyperthermia systems concerning their technical aspects, treatment outcomes and adverse events (AE’s) will be described in this review. In patients failing standard treatment who are not fit or unwilling to undergo surgery, RF-induced QHT should be considered. Besides QHT, there are more forms of treatment currently being investigated in NMIBC like EMDA and neoadjuvant intravesical chemotherapy, these require more clinical trials to determine patient selection and efficiency.
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Two Phase II studies, three Phase III and one observational study seem to justify that EMDA-MMC is a real alternative in the treatment of patients with NMIBC, especially the high risk group. The phase III studies compare EMDA-MMC with passive diffusion MMC and BCG in patients with bladder TIS. They showed EMDA MMC superiority compared to passive diffusion MMC and similar to BCG in achieving complete response at 3 and 6 months. In another randomized study on pT1 NMIBC patients, comparing a sequential scheme of BCG plus EMDA-MMC and BCG, the sequential regimen was significantly superior than BCG reducing recurrence and progression and improved overall and specific survivals. A third randomized study compared TURBT only with immediate post TURBT MMC instillation and EMDA-MMC preoperative instillation. This latter showed to be superior in recurrence prevention than the other two schemes. Tolerance to EMDA-MMC is inferior to passive diffusion MMC, but it does not reach statistical significance. In the same way, EMDA-MMC tolerance is better than BCG and there is no difference between this and the sequential scheme of BCG plus EMDA-MMC. Methodological defects observed in these studies and the fact that almost all of them come from the same group makes it necessary to reproduce this data in other centers so that this therapeutic alternative could be included in guidelines.
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Adjuvant endovesical treatment is a research field in constant exploration with the aim to minimize the risk of recurrence and progression of non muscle invasive bladder tumors. Over the last years, the administration of chemotherapy in a chemo hyperther-mia regimen has been added to the existing regimens. There are various systems for its administration, but this article focus on HIVEC (Hyperthermic IntraVEsical Che-motherapy) and its current status. In this review article we update the results of this system in the case-scenarios it has been used (preoperative with ablative intention and as adjuvant therapy with prophylactic purposes), tolerance and security issues, on-going clinical trials and future perspectives.
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OBJECTIVES: The treatment of nonmuscle invasive bladder cancer (NMIBC) continuesto be a challenge. Hyperthermia(HT) combined withintravesical chemotherapy is used to enhance the effectsof chemotherapy.METHODS: A review of the publications was carriedout to synthesize the adverse effects (AE) reported bythe use of chemohyperthermia (QHT) with Mitomycin-C(MMC). The most relevant data are exposed for each ofthe devices currently used in the QHT.RESULTS: SYNERGO®: The dropout rate variedbetween 3-40%, and the AE rate is up to 88%. The mostcommon AEs were pain (2-40%), thermal reaction ofthe posterior wall (13-100%), bladder spasms (2-32%),dysuria (3-60%) and hematuria (2-62%).COMBAT BRS®: The dropout rate is 3-11%. The AEsreported were CTCAE Grade 1-2: Pain 13-27%,bladder spasms 6-27% and hematuria 3-20% are themost relevant. In general, CTCAE grade 3-4 toxicity isnot reported.UNITHERMIA®: The dropout rate is 7-12%. The AEsdescribed are: Pain 6-23%, bladder spasms 6-23%,hematuria 9-11%, frequency 15-25% and allergy6-11%. The majority of toxicities are CTCAE grade 1-2(17-53%), with grade 3-4 in 9-15% and Grade 5 in0-2%.QHT adds little to the AEs of the treatment with MMC.It neither adds severe effects, nor increases dropoutssignificantly, and does not increase the incidence ofallergic reactions.The comparative study between BCG and QHT-MMC,is less likely to present urinary frequency, nocturia,incontinence, hematuria, fever, fatigue and arthralgia inpatients in the QHT group.CONCLUSIONS: QHT has proven to be a safealternative for the treatment of intermediate and high riskNMIBC, with AE mainly grade 1-2. The AEs reportedhave little variation with respect to the dose of MMCused, presenting different “profiles” related to the deviceused for its administration. The treatments with QHTMMCare well tolerated, without adding significantly more AEthan the instillations of MMC alone and presenting abetter toxicity profile than those reflected in the literaturewith respect to the treatment with BCG
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Neoadjuvant chemohyperthermia (QHT) with MMC has demonstrated its efficacy in NMIBC both in the level of complete response at the time of TURBT and reduction of recurrences after several years of follow up. We present our experience with this treatment.METHODS: We performed a case control study in a group of 104 patients with middle-high risk NMIBC. 43 of them received neoadjuvant recirculated intravesical QHT and 61 passively administered standard adjuvant MMC. Patient follow up was 43 months (3 - 108) evaluating their clinical efficacy and adverse effects in both groups. RESULTS: After neoadjuvant QHT, 27 patients showed CR (63%), 13 PR (30.2%) and 3 NR (6.9%). 5 year recurrence rate after QHT passive MMC were 16.2% and 26.2% respectively. No patient in the QHT group presented tumor progression compared to 5% progressions in the group treated with MMC at room temperature and 1.6% deaths due to metastatic disease. 94% QHT programmed doses were administered in comparison to 97% in the group of standard MMC. In the QHT group there were 60.5% grade 1-2 AEs in comparison with 49% in the standard MMC group (p<0.4). Likewise, 9.3% cases in the QHT group presented Grade 3 AEs versus 6.5% in the standard MMC (p<0,06).CONCLUSIONS: Recirculating neoadjuvant QHT achieves a reduction in tumor recurrence after 4 years with a similar AE rate in comparison with passive instillation of MMC.
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Disease recurrence and progression remain as significant challenges for the management of non-muscle invasive bladder cancer (NMIBC). In recent years, novel drugs and delivery systems have been investigated as strategies to reduce recurrence, progression and mortality. In this review, we focus on the role of intravesical hyperthermic chemotherapy and discuss a novel approach involving a heat-activated drug delivery system (ThermoDox®) that enables local accumulation of systemic chemotherapy.
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Bacilus Calmette-Guerin (BCG) administered intravesical is an effective therapy in non muscle invasive bladder cancer (NMIBC), but it presents limitations regarding recurrence and toxicity. For years, many case series have been published where sequential therapy with BCG and Mitomycin C (MMC) was tried. In this article, we perform a review of the data supplied by these articles with the aim to determine the safety and efficacy of combination, and what is the group of patients it should be indicated. Many studies show that combination therapy did not cause more toxicity and improved the interval free of disease with decrease of tumor progression compared to BCG or MMC monotherapy. Therefore, a combination of MMC and BCG therapy seems safe, but more clinical studies are required for a future evaluation.
