Download Bladder Cancer with Muscle Invasion

MEDICINE
REVIEW ARTICLE
Bladder Cancer with Muscle Invasion
Part 3 of the series on bladder cancer
Detlef Frohneberg
SUMMARY
Introduction: With the increasing availability of modern surgical approaches to urinary
diversion such as orthotopic bladder substitution, cystectomy represents an effective and save
procedure for local control of bladder cancer with muscle invasion, without metastatic spread.
Methods: Selective literature review and summary of interdisciplinary expertise. Results and
discussion: Regional lymph node metastases are found in up to 15% of T1 disease and are
present in 35% to 75% of T3/4 lesions depending on the extent of lymphadenectomy. Extended
lymphadenectomy is gaining in importance as an integral part of surgical treatment. For patients
ineligible for radical cystectomy due to co-morbidity, combined chemo-radiotherapy may present
an alternative, but should be preceeded by a macroscopically complete transurethral resection.
The roles of neoadjuvant and adjuvant chemotherapy have now been evaluated in metaanalyses,
which suggest benefit for both approaches. Since the benefit is smaller than expected, and in
the case of adjuvant therapy, the data are based on an insufficient patient number, its
recommendation as a standard of care is currently unjustified, and its role remains uncertain.
Dtsch Arztebl 2007; 104(13): A 868–72.
Key words: bladder cancer, cystectomy, chemotherapy, adjuvant, neoadjuvant, combined
radiochemotherapy
A
round 90% of bladder tumors are urothelial in origin. It is usual to distinguish
between papillary and solid types of tumor growth. 70% to 80% of tumors show
non-invasive papillary growth at the time of diagnosis (pTa-1). 10% to 15% of these tumors
progress to muscle invasion during the course of the disease. On the other hand some
tumors show muscle invasion at the time of diagnosis and carry a worse prognosis (pT2,
> pT2). pT1 tumors and carcinomata in situ (CIS) cannot always be clearly ascribed to one
of the above categories, in terms of tumor biology and rate of progression (diagram).
Methods
This article is based on interdisciplinary cooperation with colleagues from urooncology
and radiotherapy experienced in the treatment of bladder cancer. Data on cystectomy and
organ conserving treatments such as partial cystectomy or transurethral resection in combination
with radio or chemotherapy are based on retrospective studies. Data from randomized
studies are available for neoadjuvant and adjuvant chemotherapy of locally advanced bladder
cancer, and are cited in the references.
Radical Cystectomy
10% to 20% of bladder cancers show muscle invasion at the time of diagnosis, without
lymph node involvement or distant metastases. The treatment of choice is radical cystectomy
with bilateral pelvic lymphadenectomy.
In the man this means the removal of bladder, prostate, proximal seminiferous tubules,
distal ureters and urethra where there is urethral involvement, or where no orthoptic
bladder replacement is envisaged. Hysterectomy and the removal of the anterior portion
of the upper third of the vagina is recommended in women, due to the possibility of tumor
infiltration of these structures. Simultaneous oophorectomy is no longer standard practice.
The level of the ureteric resection is determined by the results of frozen section. The resection
margin should be free from both tumor and carcinoma in situ. If the ureter can be conserved,
the same dissection technique should be used as for radical prostatectomy, both in the interests
of urinary continence via a neobladder, and to maximize the chances of preserving potency.
The same approach to preserving the neurovascular bundle is appropriate in women.
Urologische Klinik, Städtisches Klinikum Karlsruhe GmbH, Karlsruhe: Prof. Dr. med. Frohneberg
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In men, it is obligatory to remove the prostate where there is tumor involvement, but even where
it is uninvolved, it appears wise, in order to remove completely the urothelium in this region,
to prevent recurrence and/or the development of prostate cancer. Some authorities advise
enucleation of the gland, or conservation of the posterior prostatic capsule, to preserve
potency (1). This approach is questionable in an era where neuroprotective approaches to
prostatectomy are possible, in view of the possible risk of prostate cancer or recurrence of
urothelial cancer in the proximal urethra.
The removal of the anterior proximal portion of the vagina in women is related to infiltration
depth and localization of the tumor. The removal of a healthy uterus should only be carried
out after discussion with the patient; in premenopausal women, at least one ovary should
be conserved. Urethral conservation where an orthoptic neobladder is desired follows the
same principles as in men.
Orthoptic bladder replacement is desirable as a method of urinary drainage, although
multimorbidity and age-related cognitive decline can mitigate against this. As an alternative,
a conduit attached to a bag, but without continence, may be used. Where the site of tumor
or the presence of urethral involvement renders orthoptic bladder replacement impossible,
a urinary pouch, which can be catheterized, or an ileal conduit are alternatives. The latter
requires anal sphincter continence.
Bearing in mind the available operative techniques and the possibility of orthoptic bladder
replacement, radical cystectomy is an effective and safe treatment for the local control of
non-metastasized bladder cancer with muscle invasion.
Effect of cystectomy on survival
Since the probability of metastasis correlates with the depth of infiltration, treatment effects
are presented relative to tumor spread as determined intraoperatively. The corrected 5 year
survival for patients with bladder cancer with muscle invasion type pT2 is over 89%,
according to recent studies, with a survival of 79% in patients with pT3a tumors. Survival
is markedly reduced in tumors extending beyond the bladder wall ( pT3a). Long term
survival also differs markedly according to intraoperative lymph node status (table 1). 75%
to 94% of patients with T4 tumors die within 5 years of the complications of the urothelial
cancer.
In advanced disease, cystectomy may still be useful as a palliative measure to improve
the patient's general condition, control the local tumor and remove or prevent tumor-related
complications.
DIAGRAM
Percentage distribution of histological stage of bladder cancer at
diagnosis
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Urethral recurrence
Where the resection margin is not tumor-free, primary urethrectomy is indicated. It is
essential that the urethra is included in follow-up, even though the risk of urethral recurrence
is controversial and, along with the depth of prostatic invasion, depends on the type of
urinary drainage. 11% of patients with involvement of the prostatic urethra developed urethral
recurrence, as did 1 to 4 of patients with no involvement of the prostatic urethra (3, 4).
Local recurrence
Local recurrence is defined as renewed tumor growth in the pelvis, as distinct from lymph
node metastases above the bifurcation of the iliac arteries and in the groin. Aside from the
histological tumor stage, grade, and presence of microscopic or macroscipic residual
tumor, the presence of lymph node metastases at the time of cystectomy is an important risk
factor. Early diagnosis and cystectomy, better detection of patients with a hight risk of
progression and better adjuvant or neoadjuvant treatment regimens have led to a reduction
of local recurrences in recent years to around 7% to 11% (5).
Affected lymph nodes remaining after surgery may be a source of local recurrence. For
this reason some authors recommend extended lymphadenectomy, an approach supported
by a number of retrospective studies (6–8). The value of extended lymphadenectomy is
currently under investigation in a randomized study carried out by the Arbeitsgemeinschaft
TABLE 1
Disease specific survival following radical cystectomy in urothelial carcinoma with muscle
invasion (from 2)
Tumor stage
< pT3a
N
5 year survival rate
(corrected %)
10 year survival rate
(corrected %)
374
78.9
72.9
> pT3b
312
36.8
33.3
N0
493
66.7
61.7
N+
193
31.2
27.7
pT3a, microscopic infiltration of the perivesical fat; pT3b, macroscopic infiltration of the perivesical fat; N, lymph nodes
Urologische Onkologie (AUO – Working Group for Urological Oncology) of the German
Cancer Society (Deutsche Krebsgesellschaft) (study protocol available on www.auoonline.de). The prognosis for patients with local recurrence is generally poor, with a medium
survival of 4 to 12 months.
Bladder conservation in tumors with muscle invasion
Transurethral resection with combined radio and chemotherapy
The attempt to preserve the bladder is justified where the probability of local cure
with a functionally intact bladder is high without loss of survival relative to radical
cystectomy. Neither transurethral resection alone, nor radio or chemotherapy alone
achieve adequate local control data to represent a real alternative to radical cystectomy.
These results improve markedly however where these treatment modalities are used in
conjunction (9).
Initial transurethral resection
Where the infiltration depth allows for complete tumor resection, if necessary in more than
one procedure, this should be attempted before radiochemotherapy. The following are also
favorable prognostic indicators:
> early stage of tumor (T2)
> unifocal growth
> tumor size below 5 cm
> absence of lymphatic or vascular infiltration (L0, V0)
> absence of ureteric obstruction
> absence of accompanying carcinoma in situ.
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Radiotherapy
Radiotherapy begins 2 to 4 weeks after TUR. The total dose to the 2nd order target volume
(primary tumor plus pelvic lymphatic drainage) is 45 to 50 Gy. Following this, an additional
small volume saturation dose is administered in the area of the primary tumor, up to
55.80 Gy after R0 resection or up to 59.40 Gy following R1/2 resection.
Chemotherapy
Chemotherapy has two rationales: On the one hand, it aims to potentiate radiotherapy via
the radiosensitizing effect of agents such as cusplatin and 5-fluorouracil, leading to higher
remission and tumor control rates. On the other hand, it is hoped that radiotherapy will
effectively treat occult local tumors which are present in up to 50% of patients at diagnosis.
The only randomized comparison to date showed a significant improvement in local
control when radiotherapy was combined with a chemotherapy regimen containing cisplatin
(10, 11). Caution is indicated in patients where there is no initial response to chemotherapy,
and in whom the possibility of advising cystectomy must be considered. The European
Organisation for Research and Treatment of Cancer (EORTC) has developed a study
protocol in this area, comparing bladder conservation with radical cystectomy (EORTC
Protocol 30971).
Re-staging with cystoscopic follow-up of the treatment effect, and salvage operation where appropriate
Follow-up of treatment effect with a re-staging TUR is an essential part of ongoing
management. Non-responders can be detected early and offered radical cystectomy. This
"salvage" cystectomy forms an integral part of the overall treatment plan and should not be
delayed in patients who are fit for surgery and consent to the procedure. Salvage cystectomy
is potentially curative in patients with remaining muscle invasive tumor. The 5 year
survival rates are in the region of 50%, similar to those after primary cystectomy (12).
Side effects, long term sequelae and follow-up
The acute side effects are commonly radiogenic cystitis, proctitis and diarrhea. Severe acute
side effects (grade 3 to 4) are rare (< 5% to 10 %). Severe long term effects of radiotherapy,
such as bladder contraction or bowel stenoses requiring surgery were observed in 2% and
1.5% of cases, respectively (11). Because of the risk of recurrence in the conserved organ
(30%) and the good prognosis for recurrences when thoroughly treated, regular cystoscopic
follow-up is essential. Survival rates for these patients are similar, in non-ramdomized
studies, to those for patients undergoing primary cystectomy (table 2). The ideal candidate
for organ conservation is the patient with an early, unifocal tumor who is motivated to
attend regular, and perhaps lifelong, follow-up.
Nevertheless, even this group should be offered cystectomy. Only where cystectomy is
contracindicated is an organ conserving approach realistic.
Partial cystectomy in tumors with muscle invasion
Partial cystectomy aims at the conservation of bladder function, continence and the
neurovascular bundle, as well as local tumor control. The 5 year survival rates are comparable
TABLE 2
Results of the 3 largest single institution series worldwide, on multimodal treatment of
bladder cancer
Series
Number of
patients
Complete
remission after
TUR and RCT
5 year total survival 5 year total survival
with bladder
conservation
Paris (13, 14)
120
77 %
63 %
n. a.
Massachusetts
General Hospital,
Boston (15)
190
71 % (T2)
57 % (T3–T4a)
54 %
45 %
Erlangen (11)
415
72 %
50 %
42 %
TUR, transurethral bladder tumor resection; RCT, Radiochemotherapy; T2-T4a, infiltration of the bladder muscle (T2) or adjacent organs (T4)
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with those of cystectomy, if stringent selection criteria are applied (16) – as historical case
series suggest (17–18). Nevertheless this approach should be reserved for highly selected
patients, excluding those with accompanying carcinoma in situ, or lymph node infiltration,
who are at increased risk of disease progression.
The neoadjuvant treatment of advanced bladder cancer
Adjuvant chemotherapy aims at consolidating local treatment and controlling invisible residual
tumor cells. A study by Skinner et al., which compared cystectomy alone with cystectomy
plus 4 ⫻ cyclophosphamide, adriamycin and cisplatin in 91 patients, showed disease-free
survival in 34% versus 51% and a total survival of 39% versus 44%, in favor of adjuvant
chemotherapy. Surprisingly, however, the curves for the two groups crossed after 7 years of
disease-free survival. The study showed benefit in terms of survival at 3 years for patients
with only one tumor-infiltrated lymph node, in particular (19).
Stöckle and colleagues examined the influence of adjuvant chemotherapy following
MVAC or MVEC treatment on the rate of tumor progression following radical cystectomy
and pelvic lymphadenectomy for patients with locally advanced disease (pT3b, pT4a)
and/or pelvic lymph node metastases (20) (MVAC: methotrexate, vinblastine, adriblastine,
cisplatin; MVEC: methotrexate, vinblastine, epirubicin, cisplatin). This study showed a
significant difference in progression-free survival at 3 year follow-up in favor of adjuvant
chemotherapy (13% versus 63%). Due to the small numbers, however, this study is unable
to reliably demonstrate benefit for adjuvant chemotherapy.
A later analysis with 166 patients, including the original 49, also showed significant
benefit for adjuvant chemotherapy with a disease-free 5 year survival of 26% versus 50%.
This analysis also showed that patients with a single infiltrated lymph node benefited most (21).
Freiha et al. compared cystectomy alone with cystectomy plus 4 ⫻ CMV in 50 patients
(CMV: cisplatin, methotrexate, vinblastine). Patients not randomized to receive adjuvant
chemotherapy received it as rescue medication in disease progression. A significant difference
was found in the median time to progression in favor of the adjuvant chemotherapy (12 versus
37 months). This study was also terminated early (22).
With regard to the composition of adjuvant chemotherapy, Lehmann et al. showed in a
recent study of 327 patients that the combination of cisplatin and methotrexate (CM) is not
significantly worse than MVEC, but carries a significantly reduced rate of grade 3 and 4
toxicity (23).
If the data on adjuvant chemotherapy are summarized, as in a recent metaanalysis by the
Medical Research Council (MRC)'s Advanced Bladder Cancer Trialist Group, a survival
advantage of 9% (1% to 16 %) is found at 3 years. Albeit this analysis only included 491
patients, and several studies were terminated early, with the effect that most analyses lack
the statistical power to deliver a conclusive answer. For this reason, adjuvant chemotherapy
cannot currently be regarded as standard treatment (24).
Neoadjuvant chemotherapy of advanced urothelial cancer
To date, 11 randomized studies with a total of more than 3 000 patients exist, yet the role of
this treatment remains unclear. The data on 2 688 patients from randomized trials were
summarized as part of the MRC metaanalysis (25). The treatment group enjoyed a 5%
survival advantage when compared with the control group. Tumor-related mortality is reduced
by 13% by chemotherapy. Polychemotherapy is superior to monochemotherapy
(p = 0.044). Because the differences are marginal, routine use is not advised.
Conflict of Interest Statement
The author declares that no conflict of interest exists according to the Guidelines of the International Committee of Medical
Journal Editors.
Manuscript received on 17 January 2006, final version accepted on 16 January 2007.
The author wishes to thank the following for help in preparing the manuscript: Prof. Dr. J.W. Thüroff und Dr. Ch. Wiesner, Urologische
Klinik, Johannes-Gutenberg-Universität, Mainz; Prof. Dr. K. Miller, Urologische Klinik, Charité, Campus Benjamin Franklin, Berlin;
Prof. Dr. M. Stuschke, Klinik für Strahlentherapie, Universitätsklinikum Essen; Prof. Dr. R. Sauer u. PD Dr. C. Rödel, Klinik für
Strahlentherapie, Universitätsklinikum Erlangen; Prof. Dr. Dr. h.c. H. Rübben und Dr.P.J. Goebell, Urologische Klinik, Universitätsklinikum Essen
Translated from the original German by Dr Sandry Goldbeck-Wood.
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Corresponding author
Prof. Dr. med. Detlef Frohneberg
Urologische Klinik
Städtisches Klinikum Karlsruhe gGmbH
Moltkestr. 90
76133 Karlsruhe, Germany
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