Randomised Phase Iii Studies
Numerous small, randomised, comparative studies of various combination drug regimens in advanced and metastatic TCC have been published 12, 13, 14, 15, 16, 28, 55, 56, 63, 68, 69, 70, 71. Most of them have been phase II studies, and a few have contained as many as 100 patients. Early, modest-sized phase III studies compared single-agent cisplatin with cisplatin and methotrexate or cisplatin, doxorubicin and cyclophosphamide 15, 16. They confirmed that the combinations were more toxic than
Treating Metastatic Bladder Cancer
Treatment for metastatic bladder cancer is different for each person, depending on your specific situation. Your doctor and care team will discuss different options with you, as well as the advantages and disadvantages of each type of treatment option.
The goals of most types of treatment are to slow down how fast the cancer cells are growing and to shrink the tumor as much as possible. Other important goals of treatment are to help people with bladder cancer live as long as possible and to make sure they have the best possible quality of life. Palliative care can also help relieve symptoms and treatment side effects.4
What Is The Prognosis For Metastatic Bladder Cancer
Most people with metastatic bladder cancer cannot be cured. The 5-year relative survival rates for people with distant bladder cancer, meaning the cancer has spread to distant parts of the body such as the lungs, liver, or bones, is about 5 percent. This means that people with metastatic bladder cancer are, on average, about 5 percent as likely as people who do not have this form of cancer to live for at least 5 years after being diagnosed.1,5
However, there are treatments available that can help some people with metastatic bladder cancer to live longer and improve their quality of life.1
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Chemotherapy Plus Immune Check
Article type: Review Article
Authors: Soares, Adrianaa | Carmo, Rafaelb | Rodrigues, Catarinac | Grilo, Inês Telesd | Grande, Enriquee *
Affiliations: Medical Oncology Department, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal | Medical Oncology Department, Grupo Sasse Oncologia e Hematologia , Campinas, São Paulo, Brazil | Medical Oncology Department, Centro Hospitalar de Entre Douro e Vouga, Portugal | Medical Oncology Department, Centro Hospitalar de Trás-os-Montes e Alto Douro, Portugal | Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain
Correspondence: Correspondence to: Enrique Grande, Servicio de Oncología Médica, MD Anderson Cancer Center Madrid, C/ Arturo Soria 270, 28033 Madrid, Spain. Tel.: +34917878600 Fax: +34917680681 E-mail: .
Keywords: Metastatic bladder cancer, immunotherapy, chemotherapy
DOI: 10.3233/BLC-190260
Journal: Bladder Cancer, vol. 6, no. 1, pp. 1-8, 2020
Abstract
When Do You Have It
You might have chemotherapy:
- before or after surgery
- as a main treatment, if your cancer has spread
Chemotherapy before surgery or radiotherapy can shrink the tumour. It aims to make the treatment work better. This is called neoadjuvant chemotherapy. It can lower the risk of bladder cancer coming back in the future.
Chemotherapy after surgery may help to stop the cancer coming back. This is called adjuvant chemotherapy. You might have it if you didn’t have chemotherapy before your surgery. You usually have a combination of drugs. The most common combinations include:
- gemcitabine and cisplatin
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Challenges After Imvigor130 Results To Face With The Combination Of Chemotherapy Plus Ici
The purpose of using immunotherapy with chemotherapy is to ideally potentiate the activity of both strategies. This is the first ICI-chemotherapy combination study to demonstrate an improvement in PFS over standard-of-care in first line mUC, but it has not yet been shown an impact on OS. Therefore, there are many questions and hypotheses that still need to be answered regarding the association of ICI and chemotherapy in urothelial tumors.
It is also interesting that more patients within the combination arm were ineligible for cisplatin than in the standard chemotherapy arm , which may have disadvantaged the combination arm in terms of prognosis. This is supported by the results of Bamias et al, who showed that cisplatin administration was associated with OS benefit . Other baseline characteristics in the IMvigor130 trial, such as age, PD-L1 expression, ECOG 2 and Bajorin risk factors were well balanced in the trial. In the subgroup analysis it seemed that those patients with ECOG 2, Bajorin risk factors 2, and PD-L1 low expression had worse PFS and OS compared to other patients. Definitely, these patients pose the poorer prognosis regardless of the treatment received. One question that arises from this poor prognosis subgroup is which would be the best treatment to offer to these patients.
Fig. 2
Fig. 3
Factors that may condition for therapeutic decision.
Surgery And Radiation Therapy
Endoscopic TURBT is the first-line treatment to diagnose, stage, and treat visible tumors. TURBT is not effective for CIS, because the disease is often so diffuse and difficult to visualize that complete surgical removal may not be feasible. It is critically important to surgically remove all nonmuscle-invasive disease prior to beginning intravesical therapy. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.
The EAU guidelines recommend the use of fluorescence-guided resection, as it is more sensitive than conventional white-light cystoscopy for detection of tumors. The added detection rate with fluorescence-guided cystoscopy is 20% for all tumors and 23% for CIS. The FDA has approved the use of blue-light cystoscopy with 5-aminolevulinic acid in patients suspected or known to have nonmuscle-invasive bladder cancer on the basis of prior cystoscopy.
As many as 20% of patients initially diagnosed with CIS may have unrecognized invasion beyond the lamina propria. Thus, they may not respond to intravesical therapy. These patients are candidates for radical cystectomy or radiation therapy and/or chemotherapy. Radiation therapy with or without chemotherapy is of limited benefit in patients with pure CIS but can be useful in some patients with muscle-invasive transitional cell carcinoma .
Lymph node dissection
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How Is Systemic Chemo Different From Intravesical Chemo
Although systemic chemotherapy drugs target cancer cells, all of the cells in a patients body are exposed to the medicine. In this way, systemic chemotherapy is different than another way that chemotherapy medicine can be delivered, called intravesical chemotherapy. In intravesical chemotherapy for treating early stage or non-muscle-invasive bladder cancer, the medicine is delivered directly into the bladder where it only has an effect on the cancer cells located in the lining of the bladder.
Chemotherapy In Palliative Care
Many patients with bladder cancer present with distant metastases at diagnosis or develop metastatic disease during the course of their illness. The survival time for patients with untreated metastatic bladder cancer is usually less than 6 months, and a variety of disabling symptoms can develop during this interval that disrupt quality of life.180,181 Chemotherapy may be effective in ameliorating these symptoms.
Other regimens comprising active agents with nonoverlapping toxic effects are being investigated with the aim of enhancing the therapeutic ratio. They include combinations of cisplatin with gemcitabine or paclitaxel.181 An update of a large international randomized study that compared M-VAC with gemcitabine plus cisplatin for patients with metastatic bladder cancer186,187 revealed no differences in response rate, survival rate, or quality of life between the treatment groups. However, gemcitabine plus cisplatin was significantly less toxic more patients completed the full course of treatment, fewer had significant neutropenia or sepsis, and the rate of death from side effects was lower. These findings have led to gemcitabine plus cisplatin becoming the standard of care for patients with metastatic bladder cancer.181
Bin S. Teh MD, … Arnold C. Paulino MD, in, 2008
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Mutational Signature Profiling Reaffirms The Importance Of Apobec In Uc
Mutational signatures and shared patterns of single nucleotide variants can identify potential sources of mutagenic pressure, either intrinsic or extrinsic . By performing consensus clustering of the per-sample cosine similarity to the published COSMICv3 mutation signatures, we identified two distinct sample clusters . Cluster 1 had high CS with defective DNA mismatch repair signatures, while Cluster 2 had a high CS with APOBEC activity signatures . Independently, high TMB tumors were associated with increased APOBEC activity signatures SBS2 and SBS13 , this was represented in our clustering as K2, which in addition to having increased APOBEC, had increased TMB . Cluster 2 was numerically, but not statistically enriched for TP53 mutations . TMB and both APOBEC mutational signatures were also significantly higher in the TP53 mutant samples .
Fig. 3: Mutational signature clustering and analysis reaffirms the importance of APOBEC in UC.
The CS for SBS2, but not SBS13, was significantly elevated in micropapillary histology compared to tumors with squamous differentiation or all other UC tumors . Micropapillary tumors were also significantly associated with increase POLE mutation signature versus squamous and other UC tumors . In contrast, tumors with squamous differentiation had a significantly increased cosine similarity to mismatch repair defect signatures, such as SBS44, as compared to micropapillary but not other UC tumors .
Side Effects Of Immunotherapy
Side effects of these drugs can include fatigue, loss of appetite, an allergic reaction, skin rashes and itchy skin. Since these medications work by removing the brakes on the bodys immune system, they can also cause inflammation of any normal tissue in the body. This is because the immune system can start attacking other parts of the body, which can cause serious or even life-threatening problems in the lungs, intestines, liver, hormone-making glands or other organs.
Its very important to promptly report any new side effects to your health care team, both during or after treatment with immune checkpoint inhibitors. If serious side effects do occur, treatment may need to be held or stopped and you may be provided with high doses of corticosteroids to suppress your immune system.
Prompt recognition and treatment of these side effects may lessen the severity and duration overall, so its important to report any new or unusual side effects to your care team as soon as possible.
Immunotherapy may not be recommended for all patients. Immunotherapy may also be used in combination with other treatments, such as surgery, radiation or chemotherapy. This use is currently limited to clinical trials.
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Combination Of Parp Inhibitors With Immunotherapy
Epigenetics is defined as a heritable modification to DNA without alteration in the nucleotide sequence, resulting in altered gene transcription and chromatin structure. Epigenetic modifications include DNA methylation and post-translational histone modifications involving methylation or acetylation are common in bladder tumors. Growing evidence showed that epigenetic drugs, such as DNA methyltransferase inhibitors can upregulate immune signaling through demethylation of endogenous retroviruses and cancer testis antigens. It provides a strong rationale for the combination of epigenetic drugs with ICIs . Interestingly, RRx-001, not only a new DNA damage inducer, but also an epigenetic and immunomodulatory drug, has been recently investigated as single chemotherapeutic agent to re-sensitize tumor to prior therapy . The low toxicity profile of RRx-001 differentiates this agent from conventional anticancer drugs, such as chemotherapeutics, and epigenetic agents . Indeed, RRx-001 is able to trigger DNA damage response in urothelial bladder cancer cells, reducing the DNA methyltransferase1 levels and increasing the transcriptional levels of the interferon type III and the interferon stimulated genes . Thus, it enhances the sensitivity to ICIs. Criscuolo D et al. investigated the effects of combining three classes of drugs together with epigenetic agents and immune-checkpoint inhibitors in bladder cancer for the purpose of reducing toxicity and doses of monotherapy alone .
Patient Characteristics And Outcome Parameters
The NCR database contained date of birth, vitality status, date of death, morphology, and tumour cTNM stage. By manual chart review, the following variables were extracted: treatment received, date of cystectomy, pTNMR stage after cystectomy, date start chemotherapy, kidney function at start chemotherapy, chemotherapy cycles planned, chemotherapy cycles received, complications during chemotherapy , response to chemotherapy by imaging using the Response Evaluation Criteria in Solid Tumors criteria, recurrence of disease, date of recurrence, treatment for recurrent disease. cTNM stage was checked for authenticity.
Topography and morphology were classified according to the International Classification of Diseases of Oncology and tumour stage according to the TNM classification system.
Progression-free survival was calculated as time difference between start of treatment and first radiological evidence of progression. OS was calculated as the time difference between start treatment and date of death . For BSC, date of diagnosis was used.
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New Approaches To Systemic Treatment Of Urothelial Cancer
The optimal chemotherapy regimen for TCC has yet to be defined. Recent studies have defined less toxic regimens than M-VAC, but no progress has been made in improving the survival of this disease since the introduction of the regimen more than 20 years ago. More rational, directed measures need to be incorporated into management strategies. New cytotoxic drugs show some promise but are likely to produce only modest improvements in outcomes.
When Initial Treatment Doesn’t Work
Although many patients will respond to the initial treatments weve been discussing, it doesnt work in all patients. In some patients, the disease may eventually progress after initial therapy and secondary therapy could then be offered.
Immunotherapy as a secondary treatment might be offered to you if the diseasehas progressed, despite receiving platinum-based chemotherapy.
Secondary chemotherapy would be offered to you if you are not a candidate for immunotherapy or for those of you whose bladder cancer progresses during or after immunotherapy. No single second-line chemotherapy treatment plan is considered to be the standard secondary therapy, so your oncologist will discuss plans with you.
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Treating Stage Iii Bladder Cancer
These cancers have reached the outside of the bladder and might have grown into nearby tissues or organs and/or lymph nodes . They have not spread to distant parts of the body.
Transurethral resection is often done first to find out how far the cancer has grown into the bladder wall. Chemotherapy followed by radical cystectomy is then the standard treatment.Partial cystectomy is rarely an option for stage III cancers.
Chemotherapy before surgery can shrink the tumor, which may make surgery easier. Chemo can also kill any cancer cells that could already have spread to other areas of the body and help people live longer. It can be especially useful for T4 tumors, which have spread outside the bladder. When chemo is given first, surgery to remove the bladder is delayed. The delay is not a problem if the chemo shrinks the cancer, but it can be harmful if it continues to grow during chemo. Sometimes the chemo shrinks the tumor enough that intravesical therapy or chemo with radiation is possible instead of surgery.
Some patients get chemo after surgery to kill any cancer cells left after surgery that are too small to see. Chemo given after cystectomy may help patients stay cancer-free longer, but so far its not clear if it helps them live longer. If cancer is found in nearby lymph nodes, radiation may be needed after surgery. Another option is chemo, but only if it wasn’t given before surgery.
What Are The Possible Side Effects Of Chemotherapy
Systemic chemotherapy drugs are very powerful and they can affect cells in the entire body.1 Chemotherapy drugs can have a negative effect on cells that are healthy but multiply quickly, like the cancer cells that chemotherapy drugs target. This can cause side effects related to bone marrow, hair follicles, the inside of the mouth, and the intestinal lining.
People treated with systemic chemotherapy experience different side effects depending upon their overall health, the type of chemotherapy drug, and how long the treatment lasts. Side effects that are common include:
- Nausea and vomiting
While side effects from systemic chemotherapy can be difficult, they tend to go away after the treatment is over. Your healthcare providers will talk with you about what types of side effects that you might experience from chemotherapy and about ways to potentially reduce those effects. This is not an exhaustive list of all potential side effects of systemic chemotherapy. Talk to your doctor for further information about your specific treatment.
Patients receiving systemic chemotherapy should talk to their doctor about any other medications , herbal remedies, and any supplements they are taking, as well as any other health conditions.
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Chemotherapy In Bladder Preservation Protocols For Muscle
In appropriately selected patients, bladder preservation with trimodal therapy is a potential alternative to cystectomy for the treatment of MIBC. This approach combines radiotherapy, chemotherapy, and a complete transurethral resection of the bladder tumor. Earlier studies using cisplatin alone or in combination with fluorouracil and radiation have an average response rate around 75% with 5-year survival of 50%60%, similar to cystectomy. Cisplatin and paclitaxel have also been given with radiation, however, with additional adjuvant cisplatin and gemcitabine with 5-year OS of 50%. Twice weekly gemcitabine in combination with radiotherapy has been used in a Phase 1 study with a reported 5-year bladder-intact survival of 62%, OS 76%. A Phase 2 study }NCT01495676 is recruiting for concurrent GC with radiation. The BC2001 is a Phase 3 RCT that compared radiotherapy alone to concurrent chemoradiotherapy with 5-FU and mitomycin C. Around 30% of patients underwent NACT before enrollment. The chemotherapy group had a statistically significant improvement in 2-year locoregional DFS 67% versus 54% , with a trend toward improvement in OS at 5 years were 48% versus 35% . Results are awaited from the closed Radiation Therapy Oncology Group trial }NCT00777491 comparing cisplatin and 5-FU to gemcitabine in combination with radiation. Other alternatives to cisplatin that have been reported on include capecitabine, paclitaxel, and docetaxel .