Bladder cancer continues to result in substantial morbidity and mortality for affected individuals. Advances in the management of metastatic bladder cancer have been limited. Chemotherapy with platinum-based regimes remains the mainstay of first-line treatment. Studies investigating alternative regimes have offered no survival advantage. Targeted therapies may offer benefit either as single agent or in combination with chemotherapy. Symptoms due to metastatic bladder cancer impact patients' quality of life, and therefore holistic management is vital. Such management includes radiotherapy, bisphosphonates, and the involvement of specialist palliative care services. This review will discuss the current management for metastatic bladder cancer, future potential treatment modalities, and the evidence to support the management strategies.
There were over 10,000 new cases of bladder cancer in the UK in 2008 making it the 7th commonest cancer overall. A quarter of these are muscle-invasive bladder cancers (MIBC) [
Combination chemotherapy is the treatment of choice for metastatic bladder cancer. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) was for many years the preferred regime; however, patients experienced high toxicity levels. Newer chemotherapy regimes have attempted to offer comparable or better efficacy in terms of overall survival, response rates, and time to disease progression whilst decreasing toxicity (Table
Summary of literature related to first-line chemotherapy for metastatic bladder cancer.
Sternberg et al. [ | Sternberg et al. [ | Von der Masse et al. [ | Von der Masse et al. [ | Ecke et al. [ | Bellmunt et al. [ | Bellmunt et al. [ | Dogliotti et al. [ | Dogliotti et al. [ | Dreicer et al. [ | Dreicer et al. [ | |
---|---|---|---|---|---|---|---|---|---|---|---|
Chemotherapy regime | MVAC | HD-MVAC + GCSF | MVAC | GC | GC + Pac | MVAC | M-CAVI | GC | Gem-Carbo | MVAC | Carbo-Pac |
Response Rate (%) | 58 | 72 | 45.7 | 49.4 | 64.7 | 52 | 39 | 49.1 | 40 | 35.9 | 28.2 |
Complete Response rate (%) | 11 | 25 | 11.9 | 12.2 | 29.4 | 12.5 | 0 | 14.5 | 1.8 | 12.8 | 2.6 |
Median time to progressive disease (months) | 9.6 | 11.1 | 7.4 | 7.4 | 7 | 8.3 | 7.7 | 8.7 | 5.2 | ||
Median survival (months) | 14.1 | 15.5 | 14.8 | 13.8 | 18.5 | 16 | 9 | 12.8 | 9.8 | 15.4 | 13.8 |
Toxicity | |||||||||||
Grade 3 or 4 | 62 | 20 | 82 | 71 | 41.2 | 34.6 | 45.4 | 77 | 29 | ||
Neutropenic sepsis or febrile neutropenia (%) | 26 | 10 | 12 | 1 | 32.4 | 18 | 3.2 | ||||
Drug-related | 4 | 3 | 3 | 1 | 4 | 0 | 2.3 | 2.4 |
In an attempt to offer the benefits of MVAC whilst reducing toxicity, especially neutropenic sepsis, Sternberg et al. [
Gemcitabine and cisplatin (GC) been compared with MVAC in a phase-III randomised controlled trial, which showed that GC had significantly less toxicity with significantly lower rates of neutropenic sepsis and grade 3 or 4 mucositis and a reduction in drug-related mortality, though the latter was not statistically significant [
Triplet combinations with GC have also been studied, including a single-centre study of the triplet combination of GC plus paclitaxel [
Platinum-containing chemotherapy is the gold standard for patients with metastatic bladder cancer, however, some patients have inadequate renal function or do not tolerate cisplatin, for example due to neuropathy. In these patients, carboplatin has been suggested as an alternative. Bellmunt et al. [
A further study by Carles et al. [
Potential second-line options in metastatic bladder cancer include single-agent vinflunine, taxanes and combination regimes (Table
Summary of literature related to second-line chemotherapy and targeted therapies for metastatic bladder cancer.
Chemotherapy | Targeted Therapies | ||||||||||
Bellmunt et al. [ | Bellmunt et al. [ | Joly et al. [ | Fechner et al. 2006 [ | Fechner et al. 2006 [ | Sweeney et al. [ | Hussain et al. [ | Wulfing et al. [ | Hahn et al. [ | Rosenberg et al. [ | Gomez-Abuin et al. [ | |
Chemotherapy regime | Vinflunine + Best supportive care | Best supportive care alone | Paclitaxel | Gem-Pac 3 weekly regime | Gem-Pac 2 weekly regime | Pemetrexed | Trastuzumab plus Pac, Carbo, and Gem | Lapatinib | GC + Bevacizumab | Bortezomib | Bortezomib |
Response Rate (%) | 8.6 | 0 | 9 | 50 | 38 | 27.7 | 70 | 3 | 67 | 0 | 0 |
Complete Response rate (%) | 0 | 0 | 2 | 50 | 7 | 6.4 | 11.4 | 0 | 17 | 0 | 0 |
Median time to progressive disease (months) | 3 | 11 | 6 | 9.3 | 2 | 1.4 | 1.9 | ||||
Median survival (months) | 6.9 | 4.3 | 7 | 13 | 9 | 9.6 | 14 | 4.1 | 19.1 | 5.7 | 3.5 |
Toxicity | |||||||||||
Grade 3 or 4 | 50 | 2.7 | 36 | 23 | 4.3 | 86.4 | 35 | 0 | 0 | ||
Neutropenic sepsis or febrile neutropenia (%) | 6 | 0 | 4 | 40.9 | 2 | 0 | 0 | ||||
Drug-related | 5 | 1.7 | 7 | 0 | 0 |
A phase-III multi-centre study randomised 370 patients who had previously progressed through platinum-based chemotherapy, to receive vinflunine and best supportive care versus best supportive care alone [
A phase-II study recruited 45 patients who were treated with weekly paclitaxel [
Pemetrexed with vitamin B12, folic acid, and dexamethasone prophylaxis was investigated in a phase-II study to treat 47 patients with progressive disease following adjuvant or neoadjuvant chemotherapy [
An imbalance in the equilibrium of histone acetylation has been associated with carcinogenesis and cancer progression. HDAC inhibitors (HDACis) lead to an accumulation of acetylated histone proteins in both tumour cells and in normal tissues. They activate differentiation, arrest the cell cycle in G1 and/or G2, and induce apoptosis in transformed or cancer cells. In vitro and in vivo, HDACi demonstrate antitumour activity, by leading to an accumulation of acetylated histones and cell cycle arrest and/or apoptosis of some transformed cells.
HDACi are currently being investigated in ongoing research studies both in the locally advanced and metastatic setting [
Overexpression of epidermal growth factor receptors including human epidermal growth factor receptor (EGFR/HER) has been demonstrated in bladder cancer and may offer both prognostic indicators as well as a potential targeted treatment for metastatic bladder cancer with recommendations suggesting to be used as a supplement to conventional chemotherapy.
Trials are currently ongoing; however, a small study by Peyromaure et al. [
The safety and efficacy of trastuzumab in combination with carboplatin, gemcitabine, and paclitaxel was investigated as part of a phase-II National Cancer Institute trial [
In a further phase-II study, Beuzeboc et al. [
Lapatinib has an established use in HER-2-positive breast cancer [
A study by Bochner et al. [
Inhibitors of the 26S proteaosome complex have been shown to arrest tumour spread and growth and suppress angiogenesis; therefore, it is suggested that they may offer potential therapeutic approaches. Bortezomib, a proteosome inhibitor, has been investigated in two phase-II single-arm studies to treat advanced or metastatic urothelial cancers [
Radiotherapy has several roles in the management of metastatic bladder cancer including palliation of pain secondary to bone-metastases, control of advancing pelvic pathology, and a reduction in urinary symptoms, for example haematuria. A variety of potential regimes have been investigated for the efficacy and toxicity.
An MRC BA09 study by Duchesne et al. [
Other common fractionation regimes in use are 20 Gy in 5 fractions over one week or a single 8–10 Gy fraction.
Several large studies investigating the use of radiotherapy for painful bone-metastases have been reported, comparing single with multiple fraction regimes. A study from the Bone Pain Trial working party [
Bisphosphonates, as with other cancers, have essentially three roles: the management of hypercalcaemia of malignancy, reduction in skeletal-related events in patients with bone-metastases and the management of pain related to bone-metastases. It is widely accepted that bisphosphonates reduce the risk of skeletal complications in multiple cancers, especially metastatic disease from solid tumours [
The recommended dose to prevent skeletal-related events in patients with bone-metastases is 4 mg zoledronic acid (Zometa), with the dose adjusted based on baseline creatinine clearance (CrCl) in mL/minute [
All the treatment options discussed are being given with palliative intent to achieve a degree of disease control and aid symptom management. Improving Outcomes in Urological Cancers published by the National Institute of Clinical Excellence in September 2002 stated that palliative care is an integral part of the management of patients with urological cancers and should be available if needed to provide symptom control as well as social, spiritual, and psychological support [
This belief is supported by Brierly and O’Brien [
First-line chemotherapy in the metastatic setting is GC or HD-MVAC + GCSF. The regimes offer comparable effectiveness with reduced toxicity levels compared with the traditional MVAC regime. Carboplatin-based chemotherapy regimes offer an alternative to cisplatin-based regimes where cisplatin is contraindicated. Literature reflecting second-line chemotherapy is limited and needs further investigations. The novel targeted therapies discussed may offer additional therapeutic options either in combination with chemotherapy or as single agents. Further studies would also benefit from a greater emphasis on quality-of-life measures including pain control, which in the palliative setting, is as important as the potential response to treatment or survival advantage.
First-line chemotherapy in the metastatic setting is gemcitabine plus cisplatin or high dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus granulocyte-colony-stimulating factor (GCSF).
Novel targeted therapies offer potential additional therapeutic options; however, additional research is required.
Radiotherapy either single- or multifraction regimes offer symptomatic benefits for bone pain and localised pelvic symptoms.
Patients with metastatic urothelial cancer demonstrate substantial morbidity that would benefit from close involvement with palliative care services.