An Update on Muscle Invasive Bladder Cancer and Metastatic Bladder Cancer
Bladder cancer was one of the top five leading causes of cancer death in 2015.1 Most of these cases are of urothelial histologic origin. For about 35% of patients, bladder cancer is either muscle-invasive or metastatic at disease presentation. In addition, non-muscle invasive disease can progress to become muscle-invasive bladder cancer later on in the disease course. Preceding chapters discussed the diagnosis and staging of bladder cancer. This chapter will focus on the management of muscle-invasive urothelial bladder cancer as well as metastatic bladder cancer.
Muscle Invasive Bladder Cancer
Patients with muscle-invasive bladder cancer have the best outcomes when they are treated with a multidisciplinary approach.
Neoadjuvant cisplatin-based regimens improve survival outcomes for patients with invasive bladder cancer.2,3 This has been shown in randomized trials and meta-analyses.4-9 The Advanced Bladder Cancer Meta-analysis Collaboration found a significant disease (9%) and overall survival (5%) benefit with platinum-based chemotherapy regimens.2 A recently updated meta-analysis (2016) with mature data on these randomized clinical trials revealed a 13% improvement in survival.3 Thus, neoadjuvant chemotherapy should be offered to all patients with muscle-invasive disease.
In patients who are not eligible for cisplatinum-based regimens (eg. creatinine clearance (<60 ml/min), ECOG performance status ≥2, New York Heart Association class ≥III heart failure, grade ≥2 hearing loss, ≥2 neuropathy, proceeding directly to extirpative local therapy or XRT is sometimes appropriate.10 Among the chemotherapy regimens studied, the most effective are MVAC: methotrexate, vinblastine, doxorubicin, and cisplatin and GC: Gemcitabine and Cisplatinum (note: there is no role for Carboplatin in this disease). There has been no head to head studies but some meta-analyses have shown a decreased survival benefit for GC when compared to dose-dense MVAC. Dose-dense MVAC is tolerated well and offers the advantage of shortened time for waiting to undergo surgery.11-13 Additional advantages of neoadjuvant chemotherapy include the downstaging with ≤pT1N0 (49%).12 These chemotherapy regimens not only provide an improved overall survival but also are associated with a complete pathologic response in about 25%-30% of patients.12,14 In the future molecular subtypes may play a role in determining which patients would benefit from neoadjuvant chemotherapy.15,16 For example, Seiler et al found that tumors classified as basal tumors had the most improvement in overall survival with neoadjuvant chemotherapy.15 These studies remain hypothesis generating at this point; studies to validate them are needed before they can be used in clinical practice. Until that time we, at MD Anderson, use a risk-adapted approach to avoid chemotherapy in patients who might derive minimal benefit.17 This strategy is shown in Figure 1.17
Culp et al. performed a retrospective study to define in high-risk muscle-invasive bladder cancer (≥cT3b or histologic lymphovascular invasion, micropapillary or neuroendocrine features) patients who underwent chemotherapy and compared outcomes in those who did and did not undergo neoadjuvant chemotherapy.18 This study concluded that patients who are most likely to benefit from chemotherapy are those who are high risk due to the worse prognosis compared to low-risk muscle-invasive bladder cancer.18
A few studies have evaluated the role of immunotherapy in the neoadjuvant setting. The ABACUS trial showed a downstaging of 39% and a pathologic complete response in 29% of patients 19 The PURE study also showed a pathologic complete response in 40% of patients and downstaging in 51%.20
Radical cystectomy with urinary diversion is an essential part of the curative strategy for patients with non-metastatic bladder cancer. It is a complex surgery and is often associated with morbidity; however, enhanced recovery (ERAS) programs have helped improve patient’s surgical course outcomes.21,22 ERAS programs focus on the preoperative, intraoperative, and postoperative continuum of care. Preoperative phases focus on preparation physically and mentally for surgery. Intraoperative phases work to decrease postoperative infection and limit fluid overload. Lastly, postoperative efforts are focused on early self-care and ambulation and feeding allowing for early discharge. An integral medication has been alvimopan (Entereg) in reducing the GI-related toxicity induced by opioid medications in the perioperative setting.23
Radical cystectomy should include a bilateral pelvic lymph node dissection, this should include at a minimum the standard node dissection: internal iliac, external iliac, an obturator with consideration of an extended node template in high-risk patients (to include common iliac, presacral lymph nodes).24 While several retrospective studies have shown the importance of removing more lymph node, we await the results of SWOG trial S1011 to answer whether an extended lymph node dissection is truly needed.25-29
The approach to surgery (whether open or robotic) is less important than the skill of the surgeon.30 The International Radical Cystectomy Consortium has reported that robotic cystectomy and diversions can be performed with similar outcomes to open surgery.31 The recent randomized trial comparing open to robotic cystectomy (RAZOR) showed no difference in intermediate oncologic outcomes.31 While operative time was longer with the robotic approach, there was reduced blood loss and transfusions, and shorter hospital stay.31 To date there no randomized trials comparing intracorporeal urinary diversion to open urinary diversion.
Partial cystectomy is only appropriate in a highly selected patient population such as tumor only in a bladder diverticulum or urachal adenocarcinoma. 24
The choice of urinary diversion is an important, life-altering one for patients undergoing radical surgery.32 Common urinary diversions include the ileal conduit, right-sided colon pouch (Indiana pouch) and orthotopic neobladder. Most studies have found no difference in the quality of life for the different urinary diversions, however, females may have a greater decrease in quality of life compared to men.33-35 There are certain factors which may limit continent urinary diversions such as dexterity, cognition, previous radiation, preexisting incontinence and bladder tumor proximity to the urethra. Patients should have skills to manage their urinary diversion prior to discharge from the hospital after cystectomy.24
Trimodal therapy (TMT) with chemotherapy, radiation and maximal TURBT offers a curative option to appropriately selected patients with radical cystectomy as a salvage option.36,37 It is also an option in patients with multiple medical comorbidities, or those unwilling to undergo radical cystectomy.38 Traditional selection criteria for TMT are patients with no variant histology, minimal T2 disease, no tumor associated hydronephrosis and absence of carcinoma-in-situ.38,39 Patients should not always be offered radiation in conjunction with chemotherapy when the goal is curative intent.40 A recent large retrospective study from the NCDB using a propensity-matched analysis found median overall survival 2.7 years (RC) vs 3 years (TMT).41 However, another study using the SEER-Medicare database also using a propensity-matched analysis found that radical cystectomy was less expensive and had better survival compared to TMT with almost 50% worse overall and cancer-specific survival.42
In patients with high-risk features such as ≥T3 disease and/or ≥N1 may benefit from adjuvant chemotherapy.43,44 In a recent systematic review and meta-analysis of over 1500 patients from 11 clinical trials.43 There was significant progression-free and overall survival associated with adjuvant chemotherapy compared with radical cystectomy alone with a 35% improvement in progression-free survival and 20% improvement in overall survival.43 An additional retrospective study by Galsky et al also showed a benefit in overall survival.44 Adjuvant chemotherapy regimens have been studied with the addition of adjuvant radiation, this found improved two year outcomes of locoregional recurrence-free survival of 96% compared to those without adjuvant chemotherapy and RT of 69%.45 Patients who are chemotherapy naïve seem to benefit more than patients who underwent neoadjuvant chemotherapy.46 The most benefit is again seen with cisplatinum containing regimens.47
Adjuvant radiotherapy has had limited success due to toxicity to normal structures (eg bowel), but renewed interest has shown there may be a potential role for adjuvant radiation after radical cystectomy in high-risk patients and this is an ongoing area of study.48-51 Baumann et al and Reddy et al have both published data on the contouring and target volumes of adjuvant radiation in patients after cystectomy to help alleviate some of the previous issues with post-cystectomy anatomical changes. In addition, there are multiple ongoing trials of adjuvant therapy in patients with ≥T3 disease.50
Metastatic Urothelial Cancer
Cisplatin-based regimens remain the mainstay of treatment for patients that are eligible for chemotherapy.52 The area of immunotherapy in metastatic urothelial cancer is rapidly expanding.53 In addition, for elderly patients, cisplatin-based chemotherapy regimens can be difficult to tolerate and carry a high rate of patient elected discontinuation.54 For these reasons, immunotherapy may provide a treatment option for those who cannot tolerate cisplatin therapy.
In select patients who have responded to chemotherapy, surgery may be a reasonable step, however, this is based on retrospective data, thus selection bias must heavily influence the decision on which patients may benefit from salvage surgery.55 Salvage surgery may have a higher likelihood of complications, however, this has not been an area well studied. Surgical consolidation may be reasonable in patients who have a good response to chemotherapy and have small lesions. 56 In addition, metastasectomy has been shown to be effective in solitary pulmonary lesions in retrospective studies.55,57 In a SEER-Medicare study, a select group of patients underwent metastasectomy and over one third were still alive at three years, thus prolonging cancer survival.58 In a meta-analysis, survival was improved by 37% with a metastasectomy.59
There has been a recent deluge in the realm of immunotherapy.60 Multiple drugs have been approved with agents available for patients who fail cisplatinum therapy as second-line therapy and in those who are cisplatin-ineligible patients as first-line treatment (Table 1), .61 Combinations of immunotherapy with traditional chemotherapy are currently being investigated.
It is noteworthy that the administration of these immunotherapeutic agents has also been associated with multiple forms of immune-mediated reactions (colitis, pneumonitis, thyroiditis, hypophysitis, etc.) that can be life-threatening. Patients undergoing immunotherapy have to be watched vigilantly for adverse immune-mediated reactions, if not addressed immediately, these can lead to serious adverse outcomes.
- Written by:
Janet Baack Kukreja, MD, MPH and Ashish Kamat, MD, MBBS
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- Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202-205; discussion 205-206.
- Yin M, Joshi M, Meijer RP, et al. Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer: A Systematic Review and Two-Step Meta-Analysis. Oncologist. 2016;21(6):708-715.
- Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19(10):2638-2646.
- Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50-54.
- Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76-86.
- Choueiri TK, Jacobus S, Bellmunt J, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32(18):1889-1894.
- Moore MJ, Winquist EW, Murray N, et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17(9):2876-2881.
- Dash A, Pettus JAt, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471-2477.
- Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 2011;12(3):211-214.
- Zargar H, Shah JB, van Rhijn BW, et al. Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy. J Urol. 2018;199(6):1452-1458.
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- van de Putte EE, Mertens LS, Meijer RP, et al. Neoadjuvant induction dose-dense MVAC for muscle invasive bladder cancer: efficacy and safety compared with classic MVAC and gemcitabine/cisplatin. World J Urol. 2016;34(2):157-162.
- Peyton CC, Tang D, Reich RR, et al. Downstaging and Survival Outcomes Associated With Neoadjuvant Chemotherapy Regimens Among Patients Treated With Cystectomy for Muscle-Invasive Bladder Cancer. JAMA Oncol. 2018.
- Seiler R, Ashab HAD, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol. 2017;72(4):544-554.
- McConkey DJ, Choi W. Molecular Subtypes of Bladder Cancer. Curr Oncol Rep. 2018;20(10):77.
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- Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol. 2014;191(1):40-47.
- Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). Journal of Clinical Oncology. 2018;36(15_suppl):4506-4506.
- Necchi A, Briganti A, Raggi D, et al. Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC). Journal of Clinical Oncology. 2018;36(6_suppl):TPS533-TPS533.
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- 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.
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