Multidisciplinary Guidelines for Diagnosis and Treatment of MIBC

Jeffrey M. Holzbeierlein, MD

A multidisciplinary set of guidelines for the treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) has been created as a result of a new collaboration between the American Urological Association (AUA) and several other prominent urological groups.¹The new guidelines provide a risk-stratified clinical framework to better diagnose, treat, and manage the disease.

The guideline statements included input from the AUA, American Society of Clinical Oncology, the Society of Urologic Oncology, the American Society for Radiation Oncology, and the Bladder Cancer Advocacy Network. This first-of-its-kind collaboration offers clinicians evidence-based recommendations of 3 levels (A, B, and C); clinical principle statements that all clinicians or urologists generally agree upon; and expert opinions that express the unanimous conclusions of the panelists.

There is a clinical need for improved management of patients with MIBC, as 79,030 new cases of bladder cancer and 16,870 deaths from the disease are predicted for 2017 in the United States.²“Approximately 25% of newly diagnosed patients have muscle-invasive disease, and that rate hasn’t changed over the past 25 years. In addition, the overall prognosis of patients with muscle-invasive disease has not changed in the last 30 years and is primarily based on stage,” said Jeffrey M. Holzbeierlein, MD, a member of the panel that put together the guidelines, and director of urologic oncology at the University of Kansas Medical Center, in his presentation of the new guidelines during the 2017 American Urological Association Annual Meeting.

INITIAL EVALUATION AND COUNSELING

The first series of guidelines includes statements regarding the need for staging evaluation during physical examination of patients under anesthesia. “The panel felt that this was an important component of identifying patients [whose tumors] might be resectable, and, of course, you would do this if you suspect MIBC at the time of [transurethral resection of bladder tumor (TURBT)]. Also, since there are a lot of comorbidities, this is a critical component to assess patients to determine what they might be candidates for in terms of treatment,” Holzbeierlein said.

Although imaging and lab evaluation are critical components of staging patients with MIBC, the panel did not recommend any specific imaging modalities. The panel, however, did agree that cross-section imaging of the abdomen and pelvis should be done with intravenous contrast, as well as recognized that there are no data to support any single imaging modality over another. The guidelines do not recommend PET scans, as the panel said there was insufficient evidence to support their superiority over CT scans.

They did note that PET imaging should be reserved for patients with abnormal chest, abdominal, or pelvic images that require further evaluation or in cases where a lymph node biopsy is not feasible.

Although chest imaging is somewhat controversial, the new guidelines recommend a chest CT scan if the patient has a history of smoking. “We do recognize that we are seeing increased amounts of variant histology, and when that is suspected, we recommended a review by a dedicated GU pathologist, as the definitive histology can change treatment in up to one-third of patients,” Holzbeierlein commented.

The guidelines recommend that patients receive an explanation of all treatment options that are available, including surgery, chemotherapy, and radiotherapy. “We recognize that not all clinicians have the ability to provide 3 different disciplines, but certainly 1 clinician can provide an explanation of the multidisciplinary approaches to treatment options that are available,” he said.

The implications of various treatments on quality of life should also be discussed with the patient, and this is expressed as a clinical principle in the guidelines.¹

TREATMENT

Chemotherapy

The treatment guidelines strongly recommend neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy based on 2 completed trials that showed improved survival in patients with MIBC using this treatment regimen.^3,4The panel recognized that there are currently no validated predictive factors or clinical characteristics that anticipate a patient’s response to neoadjuvant chemotherapy, but Holzbeierlein noted that there is an ongoing trial to determine these factors. He also said that the best regimen and duration for cisplatin-based chemotherapy have not yet been identified for patients with MIBC and that the decision regarding eligibility for cisplatin-based neoadjuvant chemotherapy should be based on comorbidities and performance status.

The panel did not recommend carboplatin-based chemotherapy in the guidelines. “In fact, if the patient is not eligible for cisplatin-based neoadjuvant chemotherapy, the panel recommends moving on directly to definitive locoregional therapy, such as radical cystectomy,” Holzbeierlein said. This conclusion is based on currently insufficient evidence for carboplatin as an effective neoadjuvant chemotherapy for patients with MIBC, as well as small, randomized studies in metastatic disease that suggest an inferior response.^5,6

Based on an expert opinion, the guidelines recommend moving from neoadjuvant chemotherapy to radical cystectomy as quickly as possible, between 4 and 8 weeks after the patient has completed and recovered from neoadjuvant chemotherapy. For patients who are eligible for cisplatin-based neoadjuvant chemotherapy but did not receive it and who have T3, T4, or node-positive disease, the guidelines recommend adjuvant cisplatin-based chemotherapy.

“There have never been any randomized, controlled trials that have shown a significant benefit, but the meta-analyses have suggested a benefit, and therefore we recommend this option,” Holzbeierlein commented.

RADICAL CYSTECTOMY

The guidelines strongly recommend that clinicians offer radical cystectomy with bilateral pelvic lymphadenectomy for patients with resectable nonmetastatic MIBC. The guidelines also strongly recommend that in males, radical cystectomy include removal of the bladder, prostate, and seminal vesicles. In females, the removal of the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall are recommended. “Of course, clinicians should discuss the consideration of sexual function preservation and organ preservation, such as the anterior vaginal wall, based on the patient’s specific disease characteristics,” Holzbeierlein said.

When urinary diversion is called for, it is a clinical principle that clinicians should have a discussion with the patient regarding all options, including ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions. Holzbeierlein said that although there was discussion about ways of identifying preoperatively whether a patient was a candidate for an orthotopic neobladder, the guidelines state, as a clinical principle, that clinicians verify a negative urethral margin at the time of the surgery.

For perioperative management, the panel’s opinion was that clinicians should optimize recovery from radical cystectomy by offering patients nutrition counseling or encouraging them to enroll in smoking cessation programs. The guidelines strongly recommend perioperative pharmacologic thromboembolic prophylaxis for patients undergoing radical cystectomy. This is because many of these patients have several risk factors associated with the development of a thrombosis.⁷

The guidelines also strongly recommend mu-opioid antagonist therapy for bowel recovery after surgery. It was also stated that prior to leaving the hospital, patients should be educated regarding any type of urinary diversion that they have, ideally by an enterostomal therapist if the patient has an ileal conduit. 

PELVIC LYMPHADENECTOMY

The guidelines recommend that clinicians perform a bilateral pelvic lymphadenectomy at the time of any surgery, with curative intent. “The extent of lymphadenectomy remains somewhat unknown at this time,” Holzbeierlein said. “We recommend at least removal of the external, internal, and obturator lymph nodes, and we would recommend that at least 12 lymph nodes would be removed, as this was felt to be a good surrogate for an adequate lymphadenectomy.”

BLADDER PRESERVATION

It was stated as a clinical principle that doctors should discuss bladder preservation with all patients, and for patients with newly diagnosed, nonmetastatic MIBC who desire to retain their bladder or are unfit for radical cystectomy, clinicians should offer bladder preservation therapies.

In terms of bladder preservation strategies, “The panel’s preferred strategy is using a multimodal approach, which combines maximal TURBT, systemic chemotherapy, radiation therapy, and ongoing cystoscopy, to evaluate response and identify recurrences,” Holzbeierlein said. The guidelines recommend that prior to bladder preservation therapy, all patients undergo maximal debulking TURBT and an assessment for the presence of multifocal disease, such as carcinoma in situ. However, the guidelines do not recommend TURBT and partial cystectomy for patients who are surgical candidates, nor primary radiation therapy for this patient population.

For patients with MIBC who have chosen multimodal bladder preservation therapy, the guidelines strongly recommend that clinicians offer maximal transurethral resection of the bladder tumor, chemotherapy combined with external beam radiation therapy, and planned cystoscopic reevaluation. Further, the guidelines recommend that radiation-sensitizing chemotherapy regimens include cisplatin or fluorouracil and mitomycin C. Following bladder preservation therapy, they advise that clinicians perform regular surveillance with CT scans, cystoscopy, and urine cytology.

Notably, those who are biopsy-proven complete responders to bladder-preserving protocols remain at risk for invasive and noninvasive recurrences, as well as new tumors in the upper urinary tracts, although these recurrences may be successfully managed by prompt salvage therapy, according to Holzbeierlein. For patients who have unsuccessful bladder preserving treatment, cystectomy is strongly recommended for those who qualify. If patients have nonmuscle invasive recurrences, then they can undergo TURBT with intravesical therapies.

PATIENT SURVEILLANCE AND FOLLOW-UP

When it comes to patient surveillance and follow-up, the guidelines state that for all patients, clinicians should obtain chest and cross-sectional imaging of the abdomen and pelvis with CT or MRI at 6- to 12-month intervals for 2 to 3 years and continue annually. “We do recommend cross-sectional imaging and laboratory assessments every 3 to 6 months for 2 to 3 years after cystectomy or after bladder-preservation therapy and annually thereafter,” said Holzbeierlein. If a patient has urethral remnant, those patients should be monitored. Although the data do not support a survival advantage for urethral washes,^8,9the panel concluded that those may be considered an option.

Patient survivorship is also stressed in the guidelines. Clinicians should discuss with their patients how they are coping with their bladder cancer diagnosis and treatment. “For patients who have undergone cystectomy, we recommend participating in a cancer support group, as well as adoption of healthy lifestyles,” Holzbeierlein added.

VARIANT HISTOLOGY

“Variant histology is something that is an evolving topic within the MIBC guidelines and may require diversion from these guidelines,” Holzbeierlein commented. The guidelines recommend that for patients diagnosed with variant histology, clinicians consider diverging from standard evaluation and management for urothelial carcinoma.

According to Holzbeierlein, the most appropriate care and evaluation of variant histologies could be better understood as more are recognized over time. Thus, previous recommendations may not apply to a small, but significant, number of patients.

FUTURE RESEARCH

Several other key areas deserve attention to improve care and outcomes for patients with MIBC. Enhanced detection of bladder cancer cells through imaging technologies or other means is necessary to identify patients with high-risk and advanced disease. Additionally, the growth and introduction of novel immunotherapies for treating bladder cancer has already shown much promise, with phase II and III trials demonstrating significant antitumor activity. According to Holzbeierlein, there is also a need to establish the roles of specific imaging and laboratory tests and their appropriate spacing. Future studies are needed to define patient-specific approaches to detection of MIBC, therapy, and optimal strategies for surveillance after definitive treatment.

References:

1. Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559.
2. Siegel RL, Miller KD, Jeman A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi: 10.3322/caac.21387.
3. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi: 10.1056/NEJMoa022148.
4. Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177. doi: 10.1200/JCO.2010.32.3139.
5. Dreicer R, Manola J, Roth BJ, et al. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004;100(8):1639-1645. doi: 10.1002/cncr.20123.
6. Dogliotti L, Carteni G, Siena S, et al. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007;52(1):134-141. doi: 10.1016/j.eururo.2006.12.029.
7. Forrest JB, Clemens JQ, Finamore P, et al; American Urological Association. AUA best practice statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery. J Urol. 2009;181(3):1170-1177. doi: 10.1016/j.juro.2008.12.027.
8. Lin DW, Herr HW, Dalbagni G. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol. 2003;168(3):9610963. doi: 10.1097/01.ju.0000051907.16079.63.
9. Boorjian SA, Kim SP, Weight CJ, Cheville JC, Thapa P, Frank I. Risk factors and outcomes of urethral recurrence following radical cystectomy. Eur Urol. 2011;60(6):1266-1272. doi: 10.1016/j.eururo.2011.08.030.