What are the common chemotherapy protocols for bladder cancer?

Chemotherapy Protocols for Bladder Cancer

First-Line Chemotherapy for Metastatic/Advanced Disease

Gemcitabine-cisplatin (GC) is the preferred first-line chemotherapy regimen for metastatic bladder cancer in patients with adequate renal function, having replaced MVAC as the standard of care due to equivalent efficacy with significantly less toxicity. 1

Standard First-Line Regimens

• Gemcitabine-Cisplatin (GC): This is the category 1 preferred regimen over MVAC for most patients with good performance status and preserved renal function 1, 2
• MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin): Remains a category 1 option but is less preferred due to higher toxicity compared to GC 1
• Both regimens produce similar response rates and overall survival (14-15 months), but GC demonstrates better tolerability 3, 4

Patient Selection Criteria

• Good-risk patients (those with good performance status, no visceral metastases to liver/lung/bone, and normal alkaline phosphatase or LDH) are the primary candidates for combination platinum-based chemotherapy 1
• Poor-risk patients (poor performance status or visceral disease) show poor tolerance to multiagent regimens and rarely achieve complete remissions 1

Neoadjuvant Chemotherapy (Before Cystectomy)

Cisplatin-based combination neoadjuvant chemotherapy before radical cystectomy is strongly recommended for T2-T4a muscle-invasive bladder cancer, providing a 5-6% absolute survival benefit. 1, 5, 2

Neoadjuvant Regimens

• Cisplatin-based combinations (GC or MVAC) administered for 2-3 cycles before cystectomy 1, 5
• This approach is supported by two large randomized trials and meta-analyses showing improved survival 1
• Pathologic complete response (P0) after neoadjuvant chemotherapy correlates with significantly improved overall survival 6

Adjuvant Chemotherapy (After Cystectomy)

Adjuvant chemotherapy should be considered for node-positive patients or those with high-risk features (pT3/pT4, vascular invasion), though the evidence is less robust than for neoadjuvant therapy. 1

Adjuvant Approach

• Minimum of 3 cycles of cisplatin-based combination chemotherapy for high-risk patients 5
• Patients with pathologic stage T3-T4 or nodal involvement have >50% risk of systemic relapse, making them candidates for adjuvant treatment 1
• One prospective study showed significant survival benefit with 3 cycles of M-VAC or M-VEC adjuvant chemotherapy in advanced disease (p=0.0007) 7

Radiosensitizing Chemotherapy (Concurrent with Radiation)

For bladder-preserving approaches, cisplatin-based concurrent chemoradiation is the preferred radiosensitizing strategy. 1

Radiosensitizing Regimens

First-line options:

• Cisplatin + 5-FU 1
• Cisplatin + Paclitaxel 1
• Cisplatin alone 1

Alternative regimens:

• 5-FU + Mitomycin 1
• Low-dose Gemcitabine (category 2B) 1

Technical Considerations

• Cisplatin is typically administered on days 1 and 21 during radiation therapy 1
• Radiation dose: 45 Gy to pelvis/bladder with boost of approximately 20 Gy to disease sites 1
• Concurrent chemoradiation improves local control compared to radiation alone 1

Alternative Regimens for Cisplatin-Ineligible Patients

For patients unable to tolerate cisplatin due to renal impairment or other comorbidities, carboplatin-based regimens or single-agent therapy should be used. 1

Options for Cisplatin-Ineligible Patients

• Carboplatin-based combinations 1
• Single-agent taxane (docetaxel or paclitaxel) 1
• Single-agent gemcitabine 1
• Clinical trial participation is strongly encouraged for this population 1

Second-Line Chemotherapy

Immunotherapy with checkpoint inhibitors (pembrolizumab or atezolizumab) is now the standard second-line treatment after platinum-based chemotherapy failure. 8

Second-Line Options

• PD-1 inhibitors: Pembrolizumab, Nivolumab 8
• PD-L1 inhibitors: Atezolizumab, Durvalumab, Avelumab 8
• Vinflunine is an option for second-line therapy in patients progressing on first-line platinum-based chemotherapy, producing survival benefit in eligible patients 1
• Only pembrolizumab showed overall survival difference in phase III trials 8

Active Chemotherapy Agents

The three main drug classes with established activity in bladder cancer are:

• Cisplatin (cornerstone of most regimens) 1
• Taxanes (paclitaxel, docetaxel) 1, 4
• Gemcitabine 1, 4

Additional active agents include ifosfamide, carboplatin, and vinorelbine 4

Common Pitfalls and Caveats

• Renal function assessment is mandatory before initiating cisplatin-based therapy; creatinine clearance must be determined 1
• Performance status is critical for patient selection—poor PS patients have very limited benefit from chemotherapy 1
• Cardiac disease must be considered when selecting regimens, particularly those containing doxorubicin 1
• Patients with PS 2 and poor renal function have very limited benefit from chemotherapy and require alternative strategies 1
• The optimal duration of immunotherapy treatment remains under investigation 8