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From OncoLog, August 2012, Vol. 57, No. 8

Preoperative Chemotherapy Offers Best Outcomes for Patients with Rare Bladder Cancer

By Amelia Scholtz

Graphic: Survival graphs
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.

A 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 Oncology.

Chemotherapy

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 surgery alone.

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.

Photo: CT of tumor
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).

Photo: Dr. Arlene Siefker-Radtke
“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 tolerate surgery.

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.

Moving forward

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 bladder cancer.”

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.”

 
For more information, 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.

Other articles in OncoLog, August 2012 issue:

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