1-CUP & Bladder Cancer atf.pdf recent updates

Prostate and bladder cancer

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2. •A 55-year-old female patient presents with metastasis in the liver.
Biopsy of the liver lesion reveals cells that are positive for CD7 and
TTF1+ markers, as well as CD20-. Based on the
immunohistochemical profile, which of the following is the most
likely primary site of the cancer?
•A) Breast
•B) Colon
•C) Lung
•D) Ovary
•E) PancreasAfraTafreeh.com
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8. Cancer of the Bladder and Urinary Tract

Global Considerations:
● Urothelial carcinomas of bladder and urinary tract are closely
related to tobacco smoking in the US.
● Arsenic-contaminated water and schistosomiasis parasites are
major carcinogens in developing countries.
Introduction:
● Bladder and urinary tract cancers are the second most common
genitourinary cancers, sixth most common cancer in the US.
● Accelerated understanding of the molecular basis has led to FDA
approval of several therapeutic agents since 2016.
Clinical Epidemiology and Risk Factors:
● Typical patients are older (median age at diagnosis: 73 years),
predominantly male, and Caucasian.
● Inheritable germline genetic risk factors identified in 1/7 patients.
Mutations in MLH1, MSH2, MSH6 (Lynch syndrome), PTEN (Cowden
disease), and RB1 (retinoblastoma) increase risk.
● Environmental toxic exposures like industrial dyes, arsenic, and
certain chemicals increase risk.
● Tobacco smoking is the primary risk factor; accounts for 90% of
cases. Lifestyle changes, particularly cessation of smoking, can
prevent about 1/3 of cases.
Clinical Presentation and Diagnostic Workup:
● Patients often present with painless hematuria, rarely with flank
pain or widespread metastatic disease. AfraTafreeh.com
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9. ● Initial investigations should include urine cytology and cystoscopy.
● Radiographic evaluation of the kidneys and upper urinary tract by
CT urogram is recommended.
● Urine diagnostic testing for cancer-associated chromosomal
changes, nuclear mitotic proteins, bladder tumor–associated
antigens can aid diagnosis.
● Complete endoscopic resection is essential for histologic diagnosis
and staging.
Histology:
● Urothelial carcinoma is the most common histology (90% of cases).
● Variant histologies including squamous cell carcinoma,
adenocarcinoma, small-cell carcinoma, carcinosarcoma account for
≤10% of tumors.
Molecular Biology:
● Loss of portions of chromosomes 9q and 9p are early molecular
events.
● Low-grade tumors often have alterations in the RAS/RAF signaling
pathway, with FGFR3 mutations/fusions present in 60-80% of
patients.
● High-grade invasive phenotype often has early mutations in TP53
and RB1, alterations in CDH1, increased expression of VEGFR2.
● Urothelial carcinoma of the renal pelvis and ureter may be
associated with Lynch syndrome hereditary defects.
● Genomic analysis has identified targetable genomic alterations
(e.g., FGFR3, EGFR, ERBB2, ERBB3, PIK3CA, TSC1) in 71% of patients.
● Intrinsic molecular subtypes (luminal papillary, luminal infiltrated,
luminal, basal squamous, and neuronal) identified by RNA
sequencing.

Staging and Treatment of Bladder Cancer AfraTafreeh.com
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10. Staging of Bladder Cancer
● Bladder cancer staging is based on the depth of invasion within the
bladder wall, lymph node involvement, and spread to
surrounding/distant organs.
● 75% bladder cancer cases present as non-muscle-invasive bladder
cancer (NMIBC), 18% with disease invading the muscular wall, and
3% present with metastatic spread.
● NMIBC: Tumors involving the immediate epithelial layer or
penetrating into the connective tissue below the urothelium but
not into the muscular layer (muscularis propria).
● Muscle-invasive bladder cancer (MIBC): Tumors invading
into/through the muscularis propria or into adjacent pelvic organs.
● Lymph node staging: N1 (solitary node), N2 (two nodes), or N3
(common iliac nodes). Beyond common iliac nodes is considered
metastatic (M1).
● Stages 0a–II are defined entirely by T stage in the absence of
nodal/metastatic disease.
● Stage III: Involvement of regional lymph nodes.
● Stage IV: Distant metastases.
● Survival rates: 70-90% for stage I-II, 36-50% for stage III, and 5% for
stage IV.
Treatment Approaches
Early-Stage Disease (NMIBC)
● Mainstay: Transurethral resection of bladder tumor (TURBT).
● Low-risk disease: Single chemotherapy treatment (mitomycin C,
epirubicin, or gemcitabine) instilled directly into bladder within 24
hours of TURBT.
● Intermediate-/High-risk tumors: Weekly intravesical instillations of
Bacille Calmette-Guerin (BCG) for 6 consecutive weeks.
● Recurrence after 2 courses of BCG: Cystectomy recommended. AfraTafreeh.com
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11. ● Patients unfit for/who refuse cystectomy: Non-BCG intravesical
agents or PD-1/PD-L1 inhibitors may achieve tumor responses.
Upper Tract Disease
● For low-risk tumors: Laser ureteroscopic ablation or surgical
resection and reanastomosis.
Muscle-Invasive Disease (MIBC)
● Mainstay: Maximal debulking via TURBT followed by combined-
modality therapy (chemotherapy and radiation) or
cystoprostatectomy/anterior exenteration with urinary diversion.
● Partial cystectomy: Suitable for a subset of patients with solitary, T2
tumor in the dome of the bladder.
● Cystoprostatectomy (males)/Anterior exenteration (females):
Involves removal of bladder and associated structures, with three
options to reroute urine (ileostomy, continent urinary reservoir, or
neobladder).
● Neoadjuvant/adjuvant chemotherapy utilizing cisplatin has shown
survival advantage.
High-Risk Urothelial Carcinoma of the Upper Urinary Tract
● Preferred treatment: Nephroureterectomy.
● Segmental ureterectomy: Considered for patients with decreased
renal function.
● BCG therapy via nephrostomy tube: Can be considered for CIS
patients to preserve renal function.
● Cisplatin-based neoadjuvant chemotherapy: Recommended in
national guidelines.

Metastatic Urothelial Carcinoma AfraTafreeh.com
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12. Chemotherapeutic Regimens
1. Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC)
○ Phase 3 trial: increased median overall survival from 8.2 to
12.5 months compared to cisplatin alone.
2. Cisplatin and Gemcitabine (CG)
○ Demonstrated similar overall survival to MVAC, but with more
favorable side effect profile.
○ MVAC or CG standard first-line treatments since 2000 for
suitable patients.
Patient Conditions Impacting Treatment Choice
● Only about 5% of patients with lymph node-only metastases and
good functional status can be cured (~15-20%).
● Half of patients have renal insufficiency, comorbidities, or frail
functional status, and are not suitable for cisplatin therapy.
Carboplatin-based Regimens
● Historically used for cisplatin-ineligible patients with median overall
survival rates decreased to 9.3 months.
Immune Checkpoint Inhibitors
A. PD-1/PD-L1 Inhibitors
○ Used for frontline chemotherapy-naive (atezolizumab,
pembrolizumab), frontline maintenance (avelumab), and
second-line postplatinum (pembrolizumab, nivolumab,
avelumab).
○ Tumor responses in 10–30% of patients.
○ Approved due to improved safety profiles compared to
traditional chemotherapy and prolonged durability of some
responses.
○ Reactivate a patient’s immune system to recognize and
eliminate their cancer. AfraTafreeh.com
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13. ○ Side effects include rare immune-related toxicities that can be
severe, such as colitis, pneumonitis, hepatitis, nephritis,
myocarditis, rash, hypothyroidism, Guillain-Barre syndrome,
idiopathic thrombocytopenic purpura, and adrenal
insufficiency.
Targeted Therapies
1. FGFR Tyrosine Kinase Inhibitor (Erdafitinib)
○ Used for patients with FGFR2/3 mutations or fusions,
progressive disease post-platinum therapy.
○ Resulted in tumor responses in 32% of patients, median
duration of response 5.4 months.
2. Nectin-4–Targeting Antibody-Drug Conjugate (Enfortumab Vedotin)
○ Used post both platinum-based therapy and PD-1/PD-L1
therapy, independent of tumor mutation status.
○ Observed tumor responses in 44% of patients, including
patients with liver metastases, median response duration of
7.6 months.
Future Therapies
● Novel urothelial carcinoma therapeutics are under ongoing
investigation.


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