Preoperative Chemotherapy Offers Best Outcomes for Patients with Rare Bladder Cancer
By Amelia Scholtz
|Overall (left) and disease-specific survival from the time of diagnosis with small-cell urothelial cancer in patients undergoing neoadjuvant chemotherapy and cystectomy compared with those undergoing initial cystectomy. Adapted from Lynch SP, et al. Eur Urol 2012.
combination of neoadjuvant chemotherapy and surgery provides patients
who have small-cell urothelial cancer (SCUC) with much longer survival
times than does initial surgery, the previous standard treatment.
These improved survival times were shown in a retrospective study in
which a team of investigators reviewed the records of 172 patients
treated for SCUC at The University of Texas MD Anderson Cancer Center
between 1985 and 2010. The findings were striking. The median overall
survival time for patients treated with initial surgery—which is still
considered the standard treatment at many institutions—was only 18.3
months. In contrast, the median overall survival time for patients
treated with neoadjuvant chemotherapy followed by surgery was 159.5
months—more than 13 years. Five-year disease-specific survival rates
also differed markedly: 20% for those treated with initial surgery and
79% for those who received neoadjuvant chemotherapy and surgery.
SCUC represents less than 1% of bladder cancers. The patients are
usually men between 60 and 80 years old who have a history of smoking
or contact with industrial carcinogens. Relative to other bladder
cancers, SCUC has a high potential for rapid growth and for the
development of microscopic metastases. These characteristics have made
SCUC notoriously difficult to treat.
The infrequency with which SCUC is seen by oncologists has hampered
research progress. Studies of SCUC have small patient sample sizes, and
research funding is small relative to funding for more common cancers.
Thus, the publication of a long-term retrospective study that finds
SCUC tumors to be particularly sensitive to chemotherapy is especially
noteworthy. “The study demonstrated that neoadjuvant chemotherapy
really provides an opportunity to cure people who otherwise would have
died of their cancer,” said corresponding author Arlene Siefker-Radtke,
M.D., an associate professor in the Department of Genitourinary Medical
One of the study’s other notable findings was that postoperative
chemotherapy offers little additional benefit to SCUC patients
undergoing initial surgery. One reason for the discrepancy in the
benefits of neoadjuvant (preoperative) and adjuvant (postoperative)
chemotherapy is that patients can begin chemotherapy much more quickly
than they can be scheduled and prepared for surgery. While waiting for
surgery, SCUC patients who are not undergoing chemotherapy may
experience rapid tumor growth, resulting in surgeons’ finding much more
advanced disease than clinical staging had suggested. These patients
also may develop clinically evident metastatic disease during the
postoperative recovery period—which can last 2–3 months—before adjuvant
chemotherapy begins. With these possibilities in mind, it is perhaps
unsurprising that patients who underwent surgery followed by
chemotherapy had a median overall survival time of 18.1 months, which
was not significantly different from that of patients who underwent
The benefits of neoadjuvant chemotherapy plus surgery relative to both
surgery alone and surgery followed by chemotherapy are also apparent
when one considers disease staging. Whereas 62% of patients treated
with neoadjuvant chemotherapy had their disease downstaged to stage I
or below at surgery, only 9% of patients who underwent initial surgery
had their disease similarly downstaged. Patients with lower stage
tumors at surgery have a higher likelihood of cure than do patients
with higher stage tumors.
| Left: Computed tomography shows a small-cell urothelial tumor (arrow) with lymph node metastases before neoadjuvant chemotherapy. Right: At the time of cystoprostatectomy, the patient had no tumor remaining, and the patient’s lymph node metastasis (not shown) was in complete remission.
Over the years, MD Anderson physicians have been able to refine SCUC
chemotherapy regimens to maximize their efficacy. “Initially, we were
using bladder cancer regimens for neoadjuvant chemotherapy, but then
we’d take patients to surgery and find we weren’t achieving complete
eradication of the small-cell malignancy,” Dr. Siefker-Radtke said.
This led to the development of a new standard SCUC regimen that
alternates between cycles of drugs that target small-cell tumors, such
as etoposide and cisplatin, and those that target bladder cancer, such
as ifosfamide and doxorubicin.
In addition to varying the drug types, oncologists must vary the number
of chemotherapy cycles according to the individual patient’s needs. For
most patients, four cycles of neoadjuvant chemotherapy will offer
optimal results. For patients with stage III or IV cancer, doctors aim
for around six cycles to maximize the response to therapy.
Surgery and radiation therapy
Surgery for SCUC varies less than chemotherapy. For most patients,
neo-adjuvant chemotherapy is followed by either cystectomy or
cystoprostatectomy with a lymph node dissection. Patients whose
preoperative imaging studies show lymph node involvement are offered
surgery only in the setting of a major response to chemotherapy and
typically undergo a more extensive lymph node dissection. Of the 172
patients whose cases were reviewed in the study, 125 had surgically
resectable disease (clinical stage no higher than T4aN0M0).
|“The study demonstrated that neoadjuvant chemotherapy really provides an opportunity to cure people who otherwise would have died of their cancer.”
| – Dr. Arlene Siefker-Radtke
It is important to bear in mind that not all SCUC patients are good
candidates for the combination of neoadjuvant chemotherapy and surgery.
Patients with poor kidney function, heart disease, or advanced
emphysema may not have the strength to undergo this aggressive
chemotherapy regimen or the surgery that follows it. On a positive
note, neoadjuvant chemotherapy may allow patients whose poor condition
is related to their cancer to improve in condition sufficiently to
Patients who are not good candidates for surgery may be considered for
a combination of chemotherapy and radiation. This combination is not
considered as the first option for two reasons. First, radiation
therapy does not appear to have the long-term effectiveness of surgery.
Second, radiation therapy may increase the risk of recurrence in
patients with carcinoma in situ, which is particularly common in the
bladders of people with small-cell tumors.
Results of a clinical trial of SCUC treatment conducted at MD Anderson
prior to the retrospective study suggested that radiation could have a
role in treating brain metastases. As SCUC patients survive longer,
these metastases have become more common, affecting about 50% of
survivors who had stage III or IV disease. Doctors now consider
prophylactic cranial irradiation for these patients.
So, what lies ahead for SCUC research? The nuances of tumor
classification may provide one direction for new investigations.
Puzzlingly, some bladder tumors that are not classifiable as SCUC
appear to behave much like small-cell tumors, giving researchers pause
to consider the genetic pathways involved in tumor development. Dr.
Siefker-Radtke said, “Looking at the molecular characterization of
these rare tumors and the different genes that they express might help
us to distinguish between different types of more traditional-appearing
Communication between researchers and clinicians at different treatment
centers is especially important in clinical research involving SCUC and
other rare cancers because individual institutions may see only a few
cases of a given cancer. Communication between members of
multidisciplinary treatment teams is also essential. “Centers should
develop a treatment strategy within their group and maintain cohesion
so that everyone treats these rare tumors in the same way,” Dr.
Siefker-Radtke said. “If we saw that a treatment regimen or concept
didn’t work, we would switch to a different strategy. That’s how we
developed our current chemotherapy regimen for SCUC.” Thanks to
communication across disciplines and across institutions, neoadjuvant
chemotherapy is gaining acceptance in SCUC treatment.
“There is growing awareness that neoadjuvant chemotherapy is beneficial
for patients with SCUC, and it’s been the subject of some large
meetings and panel discussions,” Dr. Siefker-Radtke said. “This
strategy is gaining traction and is becoming more accepted as the
standard in treating this rare bladder cancer.”
contact Dr. Arlene Siefker-Radtke at 713-792-2830.
FURTHER READING Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol 2012 Apr 17. [Epub ahead of print] PMID: 22564397.
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