| RE:
PHASE II TRIAL OF NEOADJUVANT GEMCITABINE AND CISPLATIN IN PATIENTS WITH
RESECTABLE BLADDER CARCINOMA
(
Download pdf )
DANIEL HERCHENHORN,
RODRIGO DIENSTMANN, FABIO A. PEIXOTO, FRANZ S. DE CAMPOS, VALDELICE O.
SANTOS, DENISE M. MOREIRA, HEDILENE CARDOSO, ISABELE A. SMALL, CARLOS
G. FERREIRA
Departments
of Clinical Oncology (DH, FAP), Clinical Cancer Research (RD, VOS, IAS,
CGF), Urology (FSC) and Radiology (DMM), National Cancer Institute, and
Eli Lilly Medical Support (HC), Rio de Janeiro, RJ, Brazil
Int
Braz J Urol, 33: 630-638, 2007
To the Editor:
Malignancy
is not aware of the artificial boundaries between surgery and oncology.
The malignant tumor lives and expands by its own rules and biological
possibilities. To approach any malignancy with curative intent, one must
be aware of these facts. A multidisciplinary approach reaching beyond
the borders of pride and enthusiasm over ones own capacity as a surgeon
or oncologist is the proper way to improve treatment options for the patient.
Because, at the end of the day, an increase in survival benefit is what
the patient is actually seeking for and mainly nothing else.
Neoadjuvant chemotherapy in muscle invasive
urothelial urinary bladder carcinoma adds a survival benefit for our patients
as we can see in a number of trials published and presented in recent
years. The ABC-group in the meta analysis from 2003 showed that clearly
with a combined hazard ratio of 0.87 in favor of the neoadjuvant regime
and an absolute benefit of 5 % at 5 years, improving survival from 45%
to 50% (1). In the second report from the very same group 2005, in which
the SWOG-trial (2) also was included, the power of the trial increased
and the hazard ratio of 0.86 was even more favorable. The absolute benefit
of 5 % at 5 years remained (3).
The two Nordic trials Nordic Cystectomy
Trial 1 and 2 constituted a large part of the mentioned ABC meta analysis.
Separately the Nordic trials were also merged into a meta analysis of
their own, published in 2004 (4). The outcome in some aspects was different
compared to the larger ABC-trial, mainly following; the ARR (absolute
risk reduction) was 8 % in the trial as a whole and the subgroup analysis
showed a distinct advantage in the T3-subgroup (UICC, 1982) with an ARR
of 11 %. The hazard ratio for the whole trial was 0.80 in favor of neoadjuvant
chemotherapy and for the T3-subgroup 0.69. Five-year overall survival
for patients with clinical T3 in the experimental arm was 48% and in the
control arm 37%. For the T2-subgroup the hazard ratio was 0.85 (but without
statistical significance).
The explanation for this outcome comparing
to the larger ABC trials was as follows; “The studies are comparatively
large and clinically homogenous since they were done within the same recruitment
areas, within a similar biological domain and cystectomy was baseline
treatment in both studies.”
The routine use of neodjuvant chemotherapy
(platinum-based combination chemotherapy) in urothelial urinary bladder
carcinoma is now standard treatment of T2b - T3b -tumors in two major
Swedish university hospitals, Karolinska University Hospital and Uppsala
University Hospital. Still one needs to address novel approaches that
are emerging. One is the use of new and more efficient chemotherapy regimes
and the other is the extent of lymph node dissection.
In the present trial of Herchenhorn et al.,
gemcitabine was combined with cisplatin, which is a relatively new constellation.
By utilizing gemcitabine, the tolerability increases and enables patients
of higher age to be treated in future trials and treatment regimes. One
of the major caveats in above-mentioned trials was the relatively low
age of the study populations, which also has been commented on previously
(5). Still in the present trial (Herchenhorn et al.), the ages were ranging
from 18-70 with a median age of 63 and it would be of interest to also
follow a population of higher age. The question of extent of lymphadenectomy
is still debated, although some prestigious investigators have utilized
their non-randomized retrospective single centre experiences to advocate
this regimen emphatically. When it comes to staging it is for sure the
best tool we have for establishing nodal status and nodal extent of the
present malignancy. Still we find ourselves in a biological dilemma. On
one hand we have patients with macrometastatic dissemination to a number
of lymph nodes heralding a generalized disease. Certainly a generalized
disease cannot be treated by local surgical resection. On the other hand
we have patients with micrometastatic disease and some proponents of extended
dissection dearly wish that surgical skills would remove that very disease.
Investigations into the immunobiology of nodal dissemination in urothelial
urinary bladder cancer has in the same time shown the existence of a strong
defense mechanism directed against the assaulting tumor dissemination
(6). Thus there is a slight risk that an overzealous removal of nodal
deposits can lead to the surgeon depriving the patient of an existent
immunological response! Randomized trials entailing the use of neaodjuvant
cisplatin combination therapy carries so far the only conclusive evidence
for improving the survival chances in our patients. It is of that reason
of great interest to follow new attempts, like the present trial, to improve
the neoadjuvant regimen in terms of tolerability and lower toxicity.
REFERENCES
1. Advanced Bladder Cancer Meta-analysis Collaboration:
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review
and meta-analysis. Lancet. 2003; 361: 1927-34.
2. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump
DL, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy
alone for locally advanced bladder cancer. N Engl J Med. 2003; 349: 859-66.
3. Advanced Bladder Cancer Meta-analysis Collaboration: Neoadjuvant chemotherapy
in invasive bladder cancer: update of a systematic review and meta-analysis
of individual patient data advanced bladder cancer (ABC) meta-analysis
collaboration. Eur Urol. 2005; 48: 202-5; discussion 205-6.
4. Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmstrom
PU; Nordic Urothelial Cancer Group: Neoadjuvant cisplatinum based combination
chemotherapy in patients with invasive bladder cancer: a combined analysis
of two Nordic studies. Eur Urol. 2004; 45: 297-303.
5. Droz JP: Editorial comment to Advanced Bladder Cancer Meta-analysis
Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update
of a systematic review and meta-analysis of individual patient data advanced
bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005; 48:
205-6.
6. Marits P, Karlsson M, Sherif A, Garske U, Thörn M, Winqvist O:
Detection of immune responses against urinary bladder cancer in sentinel
lymph nodes. Eur Urol. 2006; 49: 59-70.
Dr.
Amir Sherif
Karolinska University Hospital
Department of Urology
171 76 Stockholm, Sweden
E-mail: amir.sherif@swipnet.se
|