Neil Osterweil

March 17, 2015

HOLLYWOOD, Florida — Although there have been no major changes to the current version of the National Comprehensive Cancer Network (NCCN) guidelines for bladder cancer, several key existing recommendations have been strengthened, according to the chair of the guidelines committee.

"The three [changes] that come most to mind are new adjuvant chemotherapy in the setting of muscle-invasive bladder cancer just prior to cystectomy; strengthening the recommendation for maintenance BCG [Bacillus Calmette–Guérin] for patients who receive induction BCG for nonmuscle invasive bladder cancer; and strengthening, at least in our minds, the recommendation to combine chemotherapy with radiation for those undergoing bladder-preservation therapy for muscle-invasive bladder cancer," Peter E. Clark, MD, from the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said in an interview with Medscape Medical News.

Dr Clark discussed the state of the art in bladder cancer therapy here at the NCCN 20th Annual Conference.

However, a couple of meeting attendees had some concerns with the guidance, citing drug-supply issues with Bacillus Calmette–Guérin and a lack of proven benefit supporting the use of surgical staging to decide on perioperative chemotherapy, which is also a recommendation.

Nonmuscle Invasive

Nonmuscle invasive bladder cancer (NIMBC) is the most common form of bladder cancer, occurring in about 80% of patients, 70% of whom present with stage Ta (papillary noninvasive disease). Another 25%, however, will present with T1 disease (invasion into the bladder submucosa), and 5% will have carcinoma in situ (high-grade, noninvasive).

Bladder tumors are notoriously heterogenous, making outcomes difficult to predict, Dr Clark said. Up to 80% of patients experience recurrence after transurethral resection alone.

The primary treatment goals for NIMBC are to prevent recurrence and progression. Depending on the grade and stage of disease, options can include perioperative intravesical chemotherapy and vigilant resection.

When it comes to surgery for NIMBC, "one and done" usually won't do, Dr Clark said.

"Re-resection — going back and re-resecting in 4 weeks or so — is important for higher-grade diseases, especially high-grade T1 tumors with no muscle in the specimen," he said.

Single-dose perioperative intravesical chemotherapy plays an important role in the treatment of low-grade Ta disease, he added.

For patients with carcinoma in situ, intravesical therapy with BCG is the treatment of choice, and maintenance BCG should be considered for all patients who receive induction BCG, the guidelines say.

Indications for intravesical therapy — BCG immunotherapy or chemotherapy — include multiple tumors (more than 3), tumors larger than 3 cm, tumor recurrence on first follow-up cystoscopy, high-grade Ta tumors, positive urine cytology after complete resection, and the presence of carcinoma in situ or lymphovascular invasion.

Muscle Invasive

The gold standard of treatment for muscle invasive bladder cancer (MIBC) is radical cystectomy with bilateral pelvic lymphadenectomy.

Indications for radical cystectomy include relapsed or refractory disease within 6 months of a transurethral resection, the presence of T1 disease or re-resection (associated with an approximately 80% risk for progression), high-volume multifocal high-grade disease, T1 disease with lymphovascular invasion, and unfavorable or mixed histology (such as micropapillary disease).

There is also "excellent" level I evidence to support the use of neoadjuvant chemotherapy with a cisplatin-based multidrug regimen plus cystectomy for patients with MIBC, Dr Clark said.

The evidence is much shakier, however, for adjuvant chemotherapy in this setting, with far fewer high-quality studies supporting a potential survival benefit. "Nonetheless, the evidence suggests that chemotherapy is more frequently administered in the adjuvant setting than in the neoadjuvant setting," he said.

Adjuvant chemotherapy with a multiagent cisplatin-based regimen does, however, remain an acceptable option for patients with poor-risk disease, such as stage T3 or greater or node-positive disease, who did not receive neoadjuvant chemotherapy.

Bladder-Preservation Therapy

Bladder preservation is, of course, desirable when practical, but some patients are likely to have poor outcomes with bladder-preservation techniques. These include patients with pretreatment hydronephrosis, those who do not have apparent complete resections with transurethral resection, and patients with carcinoma in situ, Dr Clark reported.

For others, a program of carefully coordinated trimodal therapy might spare the bladder.

A typical course of bladder-preservation therapy would include maximal transurethral resection and chemoradiotherapy. The latter is typically 40 Gy external-beam radiation and concurrent cisplatin-based chemotherapy, possibly in combination with 5-fluourauracil, paclitaxel, and gemcitabine.

"Bladder preservation is feasible," said Dr Clark. "If you're going to do it, use trimodal therapy, include chemo, include your urologists, and make sure you have an interdisciplinary team to handle these cases, because they're actually quite complicated."

"Maddening and Frustrating"

There is a nationwide shortage of BCG, which makes it difficult to follow the guidelines as closely as possible, noted Judith Leary, APN, from Cooper University Hospital in Camden, New Jersey. She asked Dr Clark whether there is an adequate alternative for maintenance in patients without carcinoma in situ.

He acknowledged that the situation is "maddening and frustrating."

"What we've tried to do in the BCG shortage phenomenon is prioritize," he explained. For patients with high-grade stage Ta cancers, for example, his group might substitute intravesical mitomycin for BCG, forego maintenance in some patients, or consider cystectomy rather than additional immunotherapy or chemotherapy in patients with relapsed disease.

Leary told Medscape Medical News that she has two patients who need to be started on intravesical therapy, and that she would reluctantly have to start them on mitomycin in the absence of an adequate supply of BCG.

Muhammad Hamdan, MD, from Sparrow Hospital in Lansing, Michigan, told Medscape Medical News that he disagrees with guideline recommendations for perioperative chemotherapy based on surgical staging results.

"It's based on relying on the surgeon to decide what's the exact T stage. We have evidence that they are wrong in 30% of the cases, and we're not sure about the other 70%. So we're taking a patient from surgery and within a few hours into another procedure, intravesical chemotherapy, and that's not side-effect free," he said, adding that his preference is observation before proceeding with chemotherapy.

Neither Ms. Leary nor Dr Hamdan were involved in the development of the guidelines.

Dr Clark, Ms Leary, and Dr Hamdan have disclosed no relevant financial relationships.

National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 13, 2015

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