The timing of chemotherapy when given as an adjunct to surgery has continued to provoke much debate over several years with proponents for neoadjuvant chemotherapy justifying their position on the basis of clinical trials such as SWOG 87103 and ABC meta analysis collaboration;4, 5 whilst proponents for adjuvant chemotherapy criticise these trials (for slow and low accrual, lack of use of cisplatin/gemcitabine regimens), and also have a meta-analysis in support and prefer to offer adjuvant chemotherapy to high-risk patients such as T3 and T4 and/or node positive tumours. A search of the literature did not find strong evidence to support the use of neoadjuvant gemcitabine and cisplatin (GC) in the treatment of muscle invasive bladder cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below.
A meta-analysis of neoadjuvant chemotherapy in the form of platinum-based combination treatment found that there was an absolute survival advantage of approximately 5% at 5 years in muscle invasive bladder cancer (HR 0.86, 95% CI 0.77-0.95, p=0.003). However, none of the trials reviewed used gemcitabine and cisplatin and the most common regimen was methotrexate, vinblastine, doxorubicin and cisplatin (MVAC).6 GC has similar response rates, disease free survival (DFS) and overall survival (OS) in the metastatic setting when compared to MVAC with less grade 3/4 toxicity, especially non-haematological toxicities.7 Therefore GC is being used in the neoadjuvant setting as it has been extrapolated that it is likely to be as efficacious as MVAC. There is stronger evidence for neoadjuvant MVAC however, this regimen may be preferred due to its better toxicity profile without the need for growth factor support. There are no phase III randomised controlled trials looking at GC in the neoadjuvant setting in muscle invasive bladder cancer. Most of these are retrospective cohort studies, which show that pathological down-staging to pT0 was seen in 25.6% of patients and to less than pT2 in 46.5%.8 Pathological down-staging has been considered a surrogate marker for DFS and OS. As seen with neoadjuvant MVAC for muscle-invasive bladder cancer, of the patients who achieved pT0 at cystectomy the 5-year survival rate was 85%.3
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Herchenhorn et al 20079 |
Yes |
No |
Cisplatin 75 mg/m2 d1 and gemcitabine 1200 mg/m2 d1,8 q21 days |
Observational studies |
Pal et al 201210 |
Yes |
Not specified |
- |
|
Yeschina et al 201211 |
Yes |
Not specified |
- |
|
Scosyrev et al 201212 |
Yes |
No |
Uses split dose cisplatin (i.e. cisplatin 35 mg/m2 d1,8 and gemcitabine 1000 mg/m2 d1,8) q21 days |
|
Kaneko et al 201113 |
Yes |
No |
Cisplatin 75 mg/m2 d1 and gemcitabine 1200 mg/m2 d1,8,15 q28 days |
|
Weight et al 200914 |
No |
No |
Various regimens |
|
Dash et al 200815 |
Yes |
No |
Uses split dose cisplatin (i.e. cisplatin 35 mg/m2 d1,8 and gemcitabine 1000 mg/m2 d1,8) q21 days |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
- |
N/A |
- |
- |
BCCA |
November 2012 |
Yes |
No |
Cisplatin 70 mg/m2 d1 and gemcitabine 1250 mg/m2 d1,8 q21 days |
CCO |
- |
Yes |
No |
Cisplatin 70 mg/m2 d1 and gemcitabine 1250 mg/m2 d1,8 q21 days |
Efficacy
A summary of the evidence supporting the effect of this protocol is below.
|
Study |
No. of patients |
Control arm |
Effect |
Median overall survival |
Pal et al10 |
24 |
MVAC n=22
Other regimen n=15
|
104.3 months |
Median progression-free survival |
Herchenhorn et al9 |
21 |
- |
27 months |
Overall response rate |
Pal et al10 |
24 |
MVAC n=22
Other regimen n=15
|
25% |
Down-staging to non-muscle invasive disease (<pT2) |
Scosyrev et al12 |
25 |
135 no neoadjuvant chemotherapy |
44% |
Toxicity
A summary of the toxicities associated with this protocol are included in the table below. Only two studies reported on toxicities.
Grade 3/4 toxicity |
Study |
Incidence of event
(%) |
Neutropenia |
Herchernhorn et al9
(n=21) |
33.33 |
Thrombocytopenia |
Kaneko et al13 (n=22) |
21.4* |
Febrile neutropenia |
Kaneko et al13 (n=22) |
2.4* |
Anaemia |
Kaneko et al13 (n=22) |
2.4* |
Nausea |
Herchernhorn et al9
(n=21) |
28.6 |
Mucositis |
Kaneko et al13 (n=22) |
0* |
Rash |
Herchernhorn et al9
(n=21) |
4.8 |
* Denominator represents number of cycles for Kaneko et al13