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 8710r and meta-analysis results as published by the ABC meta analysis collaboration.r Of concern to proponents for neoadjuvant chemotherapy is difficulty giving chemotherapy in the post operative setting, whilst advocates for adjuvant chemotherapy criticise these trials for slow accrual, low patient numbers and lack of use of cisplatin/gemcitabine regimens. Proponents for adjuvant chemotherapy may prefer to offer adjuvant chemotherapy to high-risk patients such as T3 and T4 and/or node positive tumours. Adjuvant chemotherapy may also be offered regardless of philosophy if neoadjuvant therapy has not been given.
A search of the literature did not find strong evidence to support the use of dose dense MVAC for the adjuvant treatment of muscle invasive bladder cancer. The expert reference panel supported the publication of this protocol on the basis of the information summarised below. The committee was most strongly influenced by the results from the meta-analyses demonstrating an improvement in overall survival for platinum-based adjuvant chemotherapy in comparison to definitive treatment alone.rrr
A similar protocol ("classical" MVAC, 4 week cycles) has been used extensively for the treatment of advanced bladder cancer and has also been utilised in the adjuvant setting. Dose dense MVAC is preferable to classical MVAC due to its better side effect profile and trend to improved efficacy in advanced disease.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Retrospective observational studies |
Svatek et al 2010r |
Yes |
N/A |
Supports the use of adjuvant chemotherapy |
Meta-analyses |
Tjokrowidjaja et al 2013r |
Yes |
N/A |
Supports the use of adjuvant chemotherapy |
|
Leow et al 2014r |
Yes |
No |
Supports the use of adjuvant chemotherapy |
Phase III RCT |
Sternberg et alr |
Yes |
N/A |
Supports the use of adjuvant chemotherapy |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN
|
v2.2014 |
Yes |
Yes |
Recommends neoadjuvant over adjuvant therapy on basis of higher levels of evidence
3-4 cycles (dose from Sternberg et al 2001)
|
BCCA |
April 2008 |
No |
No "classical" MVAC regimen given |
Adjuvant therapy not routinely recommended |
CCO |
February 2013 |
Yes |
Yes |
3-4 cycles |
Efficacy
Initial trials comparing "classical" MVAC given neoadjuvantly and adjuvantly did not demonstrate a difference in outcomes based on timing of treatment.r Multiple trials have examined the use of adjuvant chemotherapy post cystectomy, with consistent trends towards survival but have been underpowered to demonstrate superiority to cystectomy alone. A meta-analysis in 2005 suggested an improvement in overall survival with adjuvant platinum-based chemotherapy, but that the trials on which this result is based were not robust enough to direct treatment directions.r
Two recent meta-analyses have subsequently shown improvement in outcomes with adjuvant therapy versus no adjuvant therapy.rr The total number of individual patient results available to the Leow study was double that of the 2005 meta-analysis, but involved trials still accrued patients slowly and closed early. Whilst all trials examined utilised a platinum-based regimen, and some did use "classical" MVAC, no adjuvant trial in these meta-analyses used a dose dense regimen of MVAC. Its use in the adjuvant setting is extrapolated from its superiority to "classical" MVAC and equivalence to other cisplatin containing regimens in the neoadjuvant and metastatic contexts.
Toxicity
There is no toxicity for dose dense MVAC in the adjuvant setting. Toxicity data is derived from a randomised control trial study in the metastatic setting. Treatment in this study continued until disease progression or toxicity, therefore overestimating toxicity burden.
Toxicityr |
Grade 1 or 2 (%) |
Grade 3 or 4 (%) |
Neutropenia |
42 |
20 |
Thrombocytopenia |
32 |
22 |
Mucositis |
51 |
10 |
Renal impairment |
6 |
4 |
Nausea |
66 |
36* |
Neurotoxicity |
41 |
6 |
Alopecia |
88 |
0 |
* study performed in 2001, more recent data suggests grade 3/4 nausea to be approx 5% with modern antiemetic support.r