Jean Hoffman-Censits, MD
Wm. Kevin Kelly, DO
BASICS
DESCRIPTION
• Inoperable and metastatic bladder cancers are less common presentations than noninvasive-bladder cancer.
• Though radical cystectomy for muscle-invasive bladder cancer is potentially curative, up to 50% of patients will develop recurrent disease within 2 yr.
• Most deaths from bladder cancer are from metastatic disease.
• Lymph nodes, bones, lung, liver, and peritoneum are the most common sites of metastasis from bladder cancer. The brain can also be a site, especially after systemic chemotherapy. Other unusual sites: Heart, kidney, spleen, pancreas, and reproductive system.
• The 5-yr survival for distant metastasis is 5.4%. This is in comparison to the 5-yr survival for localized bladder cancer of 70.2%.
EPIDEMIOLOGY
Incidence
• 74,690 new cases of bladder cancer will be diagnosed in 2014 with 15,580 deaths
• Bladder cancer is the 4th most common cancer diagnosed in men. Bladder cancer is much more common in men than women, whites, and those over 55 yr of age
Prevalence
An estimated 563,640 people are living with all stages of bladder cancer in US.
RISK FACTORS
• Cigarette smoking
• Chemical and occupational exposure association (aromatic amine exposure, workers in rubber, textile, leather, painting, printing, machinist, hairdressing, dry-cleaning, and trucking industries)
• Pelvic radiation and chemotherapy (Cytoxan)
Genetics
• A family history of bladder cancer increases risk, either from genetic or environmental factors
• Patients with hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) are at increased risk of developing urothelial cancers
• Genetic alterations in FGFR3/RAS, p53, EGFR, PIK3CA, Her-2, and others
PATHOPHYSIOLOGY
• Alterations in genes which contribute to toxin breakdown within the bladder (such as GST and NAT), may make bladder cancer more likely
• Tumor multifocality and high recurrence rate within the bladder, ureters, and renal pelvis with a bladder cancer history support a field effect, in part from toxin exposure
ASSOCIATED CONDITIONS
• The majority of bladder cancer diagnosed in US has no other associations.
• In Egypt and other endemic regions, chronic bladder inflammation from schistosomiasis infection can lead to squamous cell carcinoma, as can chronic bladder irritation or inflammation, such as from chronic indwelling catheter use.
GENERAL PREVENTION
• Smoking cessation
• Limit or modify chemical exposure
• Hydration may limit toxin exposure
DIAGNOSIS
HISTORY
• Many tumor recurrences are noted during routine radiographic surveillance, which is standard following radical cystectomy.
• Pain from bone metastasis, lymphatic progression in the retroperitoneum, bowel obstruction with carcinomatosis, and symptoms of visceral progression such as in the lungs and liver can be symptoms of metastatic bladder cancer.
PHYSICAL EXAM
• Most with early advanced or metastatic disease have no significant external exam findings.
– Palpable lymphadenopathy, hepatomegaly from liver involvement, as well as cachexia of malignancy can be noted.
• Leg edema with venous thromboembolism is present (incidence 1–8%); higher incidence with platinum combination therapy.
• Poor nutrition and increased abdominal girth in setting of ascites and soft tissue intra-abdominal recurrence can contribute to edema.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Lab abnormalities can include anemia of chronic disease, iron deficiency anemia in patients with longstanding hematuria, renal insufficiency in patients with ureteral obstruction, transaminitis (elevation of liver transaminases), and elevation in bilirubin in patients with liver involvement.
• Hypercalcemia is rare and associated with poor prognosis (typically associated with squamous differentiation)
• No serum tumor marker for bladder cancer.
Imaging
• Staging guidelines recommend abdomen and pelvis imaging with CT or MRI
• Imaging of the upper tract collecting system
• Chest imaging
• Bone scan if clinical suspicion of bone metastasis by pain or alkaline phosphatase elevation
• PET may be useful but not standard of care
• Documentation of normal cardiac ejection fraction required for Adriamycin
Diagnostic Procedures/Surgery
• Needle biopsy of suspected metastatic lesions
• Confirmatory needle biopsy at the time of radiographic recurrence, particularly for a patient with residual invasive or node-positive disease at cystectomy following preoperative chemotherapy, is at physician discretion
Pathologic Findings
• Urothelial (formerly transitional cell) carcinoma is the most common subtype, and for which the most data exists.
– Many patients may have urothelial cancer with squamous or other foci of dedifferentiation.
• Less common histologic subtypes are squamous cell carcinoma, adenocarcinoma, and small cell carcinoma.
DIFFERENTIAL DIAGNOSIS
• Pelvic and retroperitoneal adenopathy
– Malignancy: Lymphoma (non-Hodgkin, Hodgkin, others); metastatic (adrenal, renal, urothelial, prostate, urethral, penile, germ cell, cervical, ovarian, uterine), GI (carcinoid, lymphomas), colorectal, melanoma
– Infectious/inflammatory:
Granulomatous: TB, sarcoidosis, histoplasmosis, lymphogranuloma venereum, Castleman disease, etc.
Nongranulomatous: Viral, bacterial (if abscess in local areas), sinus histiocytosis, retroperitoneal fibrosis
– Other: Cystic retroperitoneal masses (lymphocele, urinoma, hemorrhage) aneurysms
• Bone lesions
– Congenital (bone islands, others)
– Endocrine/metabolic (hyperparathyroidism, Paget disease)
– Neoplasm primary (osteosarcoma) or secondary (prostate, breast, kidney, lung, thyroid)
– Trauma fracture (stress or healing)
– Others: Autoimmune diseases, drugs (Vitamin D, fluoride), infection (osteomyelitis), inflammatory/Idiopathic, vascular (hemangiomas, infarct)
• Pulmonary nodules
– Benign: Abscesses, septic emboli, fungal (histoplasmosis, etc.), parasites, mycobacterial, inflammatory conditions (Wegner granulomatosis), pulmonary AVM, pneumoconiosis, silicosis
– Malignant: Primary lung cancer, bladder cancer, choriocarcinoma, renal and thyroid cancer, melanoma, Kaposi’s sarcoma
TREATMENT
GENERAL MEASURES
• Treatment of urothelial (transitional cell) carcinoma with cisplatin-based chemotherapy has increased survival but cures are limited. With good performance status and renal function cisplatin-based combination chemotherapy is the initial approach (Grade 1A) (1)
• “Fitness” for cisplatin-based therapy is not well defined: Generally assessment of renal function(>60 mL/min), hearing (>25 dB at 2 contiguous frequencies), performance status (WHO/ECOG performance status 2 or less), baseline peripheral neuropathy and cardiac function (New York Heart Association [NYHA] Class II or better)
• In the setting of impaired renal function correct reversible causes (obstruction, etc.)
MEDICATION
First Line
• Cisplatin-based chemotherapy combinations are the most active and superior to carboplatin regimens. Survival outcome is similar in patients treated with standard multiday MVAC (methotrexate, vinblastine, adriamycin, cisplatin) compared to cisplatin with gemcitabine (GC), with less toxicity in the GC group (1,2)
• High-dose intensity chemotherapy with MVAC plus GMCSF (HD-M-VAC) compared to classic M-VAC led to a better overall response rate (64 vs. 50%) and improved survival (21.8% in the HD-M-VAC vs. 13.5%) at 7 yr. The toxicity profile of HD-M-VAC was superior with better dose intensity, and thus established HD-M-VAC as an alternative to standard M-VAC (3)
– MV chemotherapy is usually given every 14 days with the AC given along each 28 days
– HD-M-VAC is also referred to as “dose dense" MVAC (DDMVAC) regimen gives the same drugs at the same doses closer together, all drugs every 14 days with hematopoietic growth factor support and is recommended by the NCCN guidelines
• Adding paclitaxel to cisplatin and gemcitabine, compared to GC led to a modest but not significant improvement in survival and is not endorsed for most patients (4)
• Some typical regimens reported in the literature include
– MVAC: Methotrexate (30 mg/m2 on days 1, 15, 22), vinblastine (3 mg/m2 on days 2, 15, 22), doxorubicin (30 mg/m2 on day 2), and cisplatin (70 mg/m2), repeated every 28 days for 6 cycles
– GC: Gemcitabine (1,000 mg/m2 days 1, 8, 15) plus cisplatin (70 mg/m2 day 2), repeated every 28 days for a maximum of 6 cycles
Second Line
• There is no standard therapy for patients who have disease recurrence or progression following 1st-line cisplatin/gemcitabine or MVAC chemotherapy, and clinical trial participation is encouraged.
• Small nonrandomized studies support the use of taxanes, gemcitabine, 5-fluorouracil, methotrexate, pemetrexed, and others in the 2nd line with modest benefit of single-agent therapy.
• The substitution of carboplatin for gemcitabine in the palliative setting in the GC regimen is reasonable for those felt unfit for cisplatin.
SURGERY/OTHER PROCEDURES
• Retrospective series support consideration of salvage surgery for patients who initially present with unresectable or metastatic disease with robust chemotherapy response (5). Survival rates were consistently better in those with pathologic complete response to induction chemotherapy and in those with node only metastasis. (See Section I “Bladder cancer, urothelial, muscle invasive (clinical and pathologic T2/T3/T4)(MIBC) neoadjuvant therapy.”)
ADDITIONAL TREATMENT
Radiation Therapy
Palliative radiotherapy is an option for patients with painful bony metastasis
Additional Therapies
• Studies suggest benefit of zolendronic acid or denosumab in patients with metastatic bladder cancer to bone (6)
• Granulocyte colony-stimulating factor can help limit myelosuppression with cisplatin and others
Complementary & Alternative Therapies
Supportive care includes adequate nutrition and hydration, particularly for patients undergoing multimodality therapy
ONGOING CARE
PROGNOSIS
For patients with metastatic disease, ECOG status ≥1, hemoglobin ≤10, and visceral involvement are prognostic for overall survival (survival 14.2 mo for those with none of these features vs. 1.7 mo with all 3 features)
COMPLICATIONS
• Cisplatin: Nephrotoxicity, ototoxicity, peripheral neuropathy, fatigue
• Adriamycin (in MVAC regimen): Cardiac toxicity
• MVAC toxicity is a major concern: Myelosuppression, neutropenic fever, sepsis, mucositis, nausea, and vomiting are common (up to 54% may require readmission for toxicity)
• Neutropenia (including life-threating febrile neutropenia) associated with multimodality chemotherapy for bladder cancer. Granulocyte growth factor is standard in the high-dose intensity MVAC regimen, and is used to support patients on gemcitabine and platinum combinations
• Gemcitabine: Rash and cytopenias
• Taxanes (ie, paclitaxel): Fluid retention, neuropathy, myelosuppression
• Ureteral obstruction (tumor or lymphadenopathy) is common and can be alleviated with ureteral stenting or percutaneous nephrostomy drainage
FOLLOW-UP
Patient Monitoring
In patients with metastatic disease on chemotherapy, imaging should be performed every 2–3 mo to assess response. In patients with durable responses of chemotherapy, imaging should be done every 3 mo for the 1st 2 yr of response.
Patient Resources
• Bladder Cancer Advocacy Network
– http://www.bcan.org/
REFERENCES
1. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–3077.
2. 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.
3. Galsky MD, Chen GJ, Oh WK, et al. Comparative effectiveness of cisplatin-based and carboplatin- based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol. 2012;23:406–410.
4. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30:1107–1113.
5. Dodd P, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999;17:2546–2552.
6. Zaghloul M, Boutrus R, El-Hossieny H, et al. A prospective, randomized, placebo controlled trial of zolendronic acid in bony metastatic bladder cancer. Int J Clin Oncol. 2010;15;382–389.
ADDITIONAL READING
NCCN guidelines for Bladder Cancer, version 1.2013, http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf, Accessed January 28, 2014.
See Also (Topic, Algorithm, Media)
• Bladder Cancer, General
• Bladder Cancer, Nonurothelial
• Bladder Cancer, Squamous Cell Carcinoma
• Bladder Cancer, Urothelial, Muscle Invasive (Clinical and Pathologic T2/T3/T4) (MIBC)
• Reference Tables: TNM Classsification: Urinary Bladder Cancer
CODES
ICD9
• 188.9 Malignant neoplasm of bladder, part unspecified
• 196.9 Secondary and unspecified malignant neoplasm of lymph nodes, site unspecified
• 198.89 Secondary malignant neoplasm of other specified sites
ICD10
• C67.9 Malignant neoplasm of bladder, unspecified
• C77.9 Secondary and unsp malignant neoplasm of lymph node, unsp
• C79.89 Secondary malignant neoplasm of other specified sites
CLINICAL/SURGICAL PEARLS
• Single-agent chemotherapy provides low response rates of usually short duration.
• For 1st-line chemotherapy, performance status and the presence or absence of visceral metastases are independent prognostic factors for overall survival.
• Brisk diuresis helps limit cisplatin renal toxicity.