SECTION 1: BLADDER CANCER
CONCEPTUAL SUMMARY
Epidemiology and Risk Factors:
Risk factors include cigarette smoking (strongest modifiable risk factor), chemical exposures (aromatic amines), chronic inflammation (e.g., schistosomiasis), and prior cyclophosphamide therapy. Genetic abnormalities include deletion of chromosome 9, RAS, RB, and TP53 mutations. Nitrosoureas (carmustine) do NOT cause bladder cancer — this is a common distractor. Drinking plenty of fluids is NOT an established preventive measure.
Staging and Initial Workup:
Diagnosis begins with cystoscopy and TURBT. For T1 high-grade disease where muscle is NOT present in the TURBT specimen, a repeat TURBT within 2–6 weeks is MANDATORY before starting intravesical therapy — to confirm no muscle invasion (rule out understaging to T2).
Non-Muscle Invasive Bladder Cancer (NMIBC):
- Carcinoma in situ (CIS/Tis) is high-risk NMIBC. Standard treatment: intravesical BCG (Bacillus Calmette-Guérin) — the only FDA-approved and guideline-endorsed first-line therapy for CIS. Induction: 6 weekly instillations. Maintenance BCG improves long-term outcomes. BCG is superior to intravesical mitomycin for CIS — mitomycin is an alternative only if BCG is not tolerated. Systemic chemotherapy is NOT indicated for NMIBC — it is reserved for muscle-invasive (T2+) or metastatic disease. Pembrolizumab is reserved for BCG-unresponsive CIS in patients who refuse or cannot undergo cystectomy.
- BCG-Refractory/Unresponsive Disease: BCG-unresponsive definitions: CIS recurrence within 12 months of BCG, or papillary recurrence within 6 months. Options: cystectomy (gold standard for high-risk NMIBC), pembrolizumab (FDA-approved for BCG-unresponsive CIS), nadofaragene firadenovec, intravesical gemcitabine. Cisplatin-based systemic chemotherapy has NO role in BCG-refractory NMIBC.
Muscle-Invasive and Metastatic Disease:
- Cisplatin eligibility criteria: CrCl ≥ 60 mL/min required. CrCl < 50 mL/min = cisplatin-INELIGIBLE → use carboplatin-based regimens.
- Cisplatin-eligible patients: ddMVAC or gemcitabine/cisplatin are the preferred first-line options.
- Carboplatin should NOT replace cisplatin in cisplatin-eligible patients with good renal function.
- Cisplatin-ineligible patients: gemcitabine + carboplatin followed by avelumab maintenance (JAVELIN Bladder 100 — showed OS benefit regardless of PD-L1 status).
- Pembrolizumab first-line monotherapy: reserved for patients ineligible for ANY platinum-based regimen.
- Atezolizumab first-line monotherapy: reserved for cisplatin-ineligible patients with PD-L1 IC ≥ 5% or those unfit for any platinum.
- Enfortumab vedotin + pembrolizumab: now integrated into first-line therapy for metastatic disease; enfortumab vedotin alone is NOT first-line.
- Avelumab maintenance: standard after platinum-based chemotherapy with stable disease or better; begin 4–10 weeks after last chemotherapy; no PD-L1 testing required.
- Second-line after platinum: erdafitinib (for FGFR2/3 alterations), pembrolizumab, nivolumab, enfortumab vedotin.
- FGFR inhibitor for FGFR2/3-altered urothelial carcinoma after platinum failure. FGFR2/3 testing (NGS) is MANDATORY before treatment.
- Key toxicities: ocular toxicity (central serous retinopathy, blurred vision — up to 50% of patients; requires baseline and monthly ophthalmologic exams) and HYPERPHOSPHATEMIA (NOT hypophosphatemia — due to on-target FGFR inhibition). NOT approved for first-line therapy.
Bladder-Preservation: For T2 muscle-invasive disease in patients refusing or ineligible for cystectomy: chemoradiation with cisplatin + 5-FU (or mitomycin) is the preferred bladder-sparing approach.
PRACTICE QUESTIONS — BLADDER CANCER
CT is a 71-year-old man with Tis (carcinoma in situ), non-muscle-invasive urothelial carcinoma diagnosed after TURBT and single-dose intravesical chemotherapy. What is the best treatment option for CT at this time?
A. Intravesical Bacillus Calmette-Guérin (BCG)
B. Intravesical mitomycin
C. Systemic gemcitabine + cisplatin
D. Pembrolizumab
Explanation: BCG is the gold standard and only FDA-approved first-line therapy for CIS (Tis) — high-risk NMIBC. It reduces progression risk by approximately 50% compared to chemotherapy and achieves complete response in ~70% of patients. Induction consists of 6 weekly intravesical instillations, followed by maintenance BCG (3-week courses at months 3, 6, 12, 18, 24, and 36). Intravesical mitomycin (option B) is inferior to BCG for CIS and is an alternative only if BCG is not tolerated. Systemic gemcitabine + cisplatin (option C) is reserved for muscle-invasive (T2+) or metastatic disease — not appropriate for NMIBC. Pembrolizumab (option D) is considered only if BCG fails and cystectomy is not an option.
[/expand]A 62-year-old man with gross hematuria undergoes cystoscopy revealing a sessile bladder tumor. TURBT pathology shows high-grade urothelial carcinoma invading the lamina propria (T1), but NO muscle is included in the specimen. Which therapy would you recommend?
A. Repeat staging with transurethral resection of bladder tumor (TURBT)
B. Intravesical BCG
C. Watchful waiting
D. Chemoradiation
E. Cystectomy
Explanation:
- T1 high-grade urothelial carcinoma is high-risk NMIBC. However, the absence of muscle (muscularis propria) in the initial specimen means the stage cannot be reliably confirmed — the patient may be understaged (T2 muscle-invasive disease may have been missed).
- A repeat TURBT within 2–6 weeks is MANDATORY to confirm absence of muscle invasion and ensure complete resection before starting intravesical
BCG. - Intravesical BCG (option B) is appropriate after confirming no muscle invasion — not before.
- Watchful waiting (option C) is unacceptable for high-grade T1 disease due to high progression risk.
- Chemoradiation (option D) is for T2+ disease.
- Cystectomy (option E) may be needed if repeat TURBT shows upstaging, but is not the first step.
A 69-year-old man with T1 bladder cancer who was treated with BCG shows residual urothelial carcinoma on repeat TURBT (muscularis propria IS present in specimen, confirming non-muscle-invasive T1 disease). Which treatment would NOT be considered for his BCG-refractory bladder cancer?
A. Cystectomy
B. Pembrolizumab
C. Cisplatin
D. Intravesical gemcitabine
Explanation: Cisplatin-based systemic chemotherapy has absolutely NO role in BCG-refractory non-muscle-invasive (T1) bladder cancer. It is used for muscle-invasive (T2+) or metastatic disease only. Cystectomy (option A) is the gold standard for BCG-refractory high-risk NMIBC. Pembrolizumab (option B) is FDA-approved for BCG-unresponsive CIS ± papillary tumors in patients ineligible for or refusing cystectomy. Intravesical gemcitabine (option D) is an acceptable bladder-sparing alternative for BCG-refractory disease.
[/expand]CT progressed to muscle-invasive urothelial carcinoma with distant metastases. PD-L1 CPS = 10%. ECOG PS = 0. CrCl is now 40 mL/min. Which therapy would be most appropriate at this time?
A. Pembrolizumab
B. Gemcitabine/carboplatin followed by avelumab maintenance
C. Gemcitabine/cisplatin followed by avelumab maintenance
D. Enfortumab vedotin
Explanation: CT has a CrCl of 40 mL/min — below the 60 mL/min threshold required for cisplatin — making him cisplatin-INELIGIBLE. The correct first-line regimen is gemcitabine + carboplatin (the carboplatin-based alternative), followed by avelumab maintenance upon achieving stable disease or better (JAVELIN Bladder 100 trial — 31% OS benefit). Pembrolizumab monotherapy (option A) is first-line only for patients ineligible for ANY platinum regimen — CT can receive carboplatin, making combination chemotherapy preferred. Gemcitabine/cisplatin (option C) is contraindicated due to renal impairment. Enfortumab vedotin (option D) is not approved as monotherapy in the first-line setting — it is used in combination with pembrolizumab or in later lines.
[/expand]CT (same patient) has metastatic disease with pelvic metastases, PD-L1 tumor-infiltrating immune cells covering 2% of tumor area, and excellent renal function with ECOG 0. Which therapy would be most appropriate at this time?
A. Atezolizumab
B. Nivolumab
C.Gemcitabine/carboplatin
D. Dose-dense MVAC (ddMVAC)
Explanation: CT has metastatic urothelial carcinoma with excellent performance status and renal function — making him fully cisplatin-eligible. First-line options for cisplatin-eligible patients include ddMVAC or gemcitabine/cisplatin. Carboplatin should NOT replace cisplatin in patients who are cisplatin-eligible. Atezolizumab in the first-line setting (option A) is only for cisplatin-ineligible patients with PD-L1 IC ≥ 5% — CT's tumor has only 2% IC expression, which does not meet this threshold. Nivolumab monotherapy (option B) is a second-line option after platinum failure. Gemcitabine/carboplatin (option C) is appropriate only for cisplatin-ineligible patients — CT is eligible.
[/expand]A 65-year-old woman with metastatic bladder cancer, hypertension, chronic kidney disease (baseline creatinine = 2), PD-L1 < 1%, and an FGFR2 mutation. What is the appropriate first-line treatment?
A. Dose-dense MVAC (ddMVAC) with growth factor support
B. Carboplatin + gemcitabine
C. Pembrolizumab
D. Erdafitinib
E. Enfortumab vedotin
Answer: B. Carboplatin + gemcitabine
Explanation: This patient has significant renal impairment (creatinine = 2) indicating cisplatin ineligibility. The appropriate first-line regimen is gemcitabine + carboplatin. Pembrolizumab monotherapy (option C) is only first-line for patients ineligible for ANY platinum regimen — this patient can receive carboplatin. Erdafitinib (option D) is FDA-approved for FGFR2/3-altered tumors but only after platinum FAILURE — not as first-line therapy. Enfortumab vedotin (option E) is used in combination with pembrolizumab as a first-line alternative, or in later lines after platinum failure; the question context does not support this as the most straightforward answer here. ddMVAC (option A) contains cisplatin — contraindicated with significant renal impairment.
[/expand]An 84-year-old man with metastatic bladder cancer and diabetic neuropathy was treated with gemcitabine/carboplatin (cisplatin-ineligible due to neuropathy). After 6 cycles, imaging shows partial response. He has excellent functional status. What is the recommended next management step?
A. Two additional cycles of gemcitabine/carboplatin
B. Switch carboplatin to cisplatin
C. Avelumab maintenance
D. NGS with PD-L1 testing
E. Surveillance — immunotherapy at progression
F. Hospice
Explanation: The JAVELIN Bladder 100 trial established avelumab maintenance as the standard of care for patients who achieve stable disease or better after 4–6 cycles of first-line platinum-based chemotherapy. Avelumab maintenance demonstrated a 31% risk reduction in overall survival compared to best supportive care, regardless of PD-L1 status. It is started 4–10 weeks after the last chemotherapy dose. Continuing chemotherapy beyond 6 cycles (option A) increases toxicity without proven additional benefit. Switching to cisplatin (option B) is contraindicated due to pre-existing neuropathy. NGS/PD-L1 testing (option D) should not delay starting maintenance therapy. Waiting for progression (option E) is inferior to early maintenance. Hospice (option F) is inappropriate for a patient with excellent performance status who responded to therapy.
[/expand]Which of the following is correct about erdafitinib therapy? (Choose 2)
A. It may cause hypophosphatemia
B. Vision disorders is a major concern
C. FGFR2/3 alterations should be tested before treatment
D. It is approved for first-line treatment in cisplatin-ineligible patients
Explanation: Option B is correct — ocular toxicity including central serous retinopathy and blurred vision is a class effect of FGFR inhibitors occurring in up to 50% of patients, requiring baseline and monthly ophthalmologic exams. Option C is correct — erdafitinib is only FDA-approved for tumors with FGFR2/3 genetic alterations (mutations or fusions), confirmed by NGS testing before initiation. Option A is INCORRECT — erdafitinib causes HYPERPHOSPHATEMIA (not hypophosphatemia) due to on-target FGFR inhibition; phosphate levels must be monitored weekly for 1 month then monthly. Option D is INCORRECT — erdafitinib is approved only after platinum failure (second-line); it is not currently approved for first-line use.
[/expand]Which of the following is NOT correct regarding bladder cancer risk?
A. Cigarette smoking, some chemicals, and chronic inflammation are risk factors
B. Del chromosome 9, RAS, RB, and TP53 are genetic abnormalities in the disease
C. Nitrosoureas like carmustine may cause disease
D. A person is advised to drink lots of fluids to avoid risk
Explanation: Nitrosoureas such as carmustine are NOT associated with bladder cancer. The chemotherapy most strongly associated with bladder toxicity (hemorrhagic cystitis) and bladder cancer risk is cyclophosphamide and ifosfamide, through their toxic metabolite acrolein. Options A and B are correct — smoking, chemical exposures, chronic inflammation, and specific genetic abnormalities (del chromosome 9, RAS, RB, TP53) are all established risk factors. Option D is actually correct epidemiologically — adequate fluid intake helps dilute carcinogens in the urine and has been suggested as a preventive measure in some guidelines, making option C the incorrect statement about bladder cancer risk.
[/expand]A 54-year-old man with muscle-invasive (T2) bladder cancer who strongly prefers to avoid a urostomy. What would be the optimal management of his bladder cancer?
A. Cystectomy with ileal conduit
B. Repeat TURBT and BCG
C. Chemoradiation with cisplatin and 5-fluorouracil (5-FU)
D. Immune-checkpoint inhibitor therapy
E. Surveillance
Explanation: This patient has T2 muscle-invasive bladder cancer (MIBC) and strongly prefers to avoid a urostomy — making bladder preservation the priority. Chemoradiation (trimodality therapy: maximal TURBT + concurrent cisplatin-based chemoradiation) is the guideline-recommended bladder-sparing option for selected T2–T4a MIBC patients. Cisplatin + 5-FU is an established radiosensitizing regimen for this approach. Cystectomy with ileal conduit (option A) requires a urostomy — directly against the patient's preference. Repeat TURBT + BCG (option B) is for non-muscle-invasive disease — not appropriate for T2 MIBC. Checkpoint inhibitor therapy (option D) is for metastatic or BCG-refractory NMIBC. Surveillance (option E) is inappropriate for muscle-invasive disease.
[/expand]SECTION 2: RENAL CELL CARCINOMA (RCC)
CONCEPTUAL SUMMARY
Overview: RCC is the most common kidney cancer (~90% of cases), arising from the renal tubular epithelium. Clear cell RCC (ccRCC) is the most common subtype (~75–80%). Other subtypes include papillary, chromophobe (associated with Birt-Hogg-Dubé syndrome and FLCN mutations), and collecting duct. Classic triad (flank pain, hematuria, abdominal mass) is rare — most cases are incidentally discovered.
Risk Factors: Smoking, obesity, hypertension, male sex, older age, VHL mutations, chronic kidney disease.
Genetic Associations:
- VHL gene → clear cell RCC (most common);
- mTOR pathway mutations → chromophobe and tuberous sclerosis-related RCC;
- FLCN (folliculin) mutations → Birt-Hogg-Dubé syndrome → chromophobe RCC + pneumothoraces + skin fibrofolliculomas;
- MET mutations → hereditary papillary RCC;
- FH (fumarate hydratase) → hereditary leiomyomatosis and RCC (aggressive papillary type).
- RB gene is NOT classically associated with RCC — it is linked to retinoblastoma and osteosarcoma.
Treatment (Localized Disease):
- Partial nephrectomy is preferred for T1a (≤ 4 cm) tumors — preserves renal function. Radical nephrectomy for larger or non-amenable tumors. NO adjuvant TKI therapy is indicated for Stage I.
- Adjuvant therapy for high-risk (Stage III or higher): pembrolizumab (Category 2A — improves DFS, OS data not mature) is preferred over sunitinib. Adjuvant sunitinib is FDA-approved but is Category 3 — improves only DFS, NOT overall survival.
IMDC/Karnofsky Risk Stratification (for Metastatic ccRCC):
- Favorable (good) risk: 0 risk factors, Karnofsky ≥ 80%, all labs normal (Hgb, Ca, ANC, platelets, SCr within normal range), time to recurrence > 1 year from nephrectomy.
- Intermediate risk: 1–2 risk factors (including anemia, hypercalcemia, elevated ANC/platelets, low Karnofsky < 80%, time to recurrence < 1 year).
- Poor risk: ≥ 3 risk factors.
Risk Factors for IMDC Scoring: Low Karnofsky (< 80%), anemia, hypercalcemia (corrected Ca > ULN), thrombocytosis, neutrophilia, time from nephrectomy to systemic therapy < 1 year.
First-Line Treatment (Metastatic ccRCC):
All risk groups — IO/TKI combinations are preferred:
- lenvatinib + pembrolizumab (Category 1 for all risk groups),
- axitinib + pembrolizumab (Category 1 for all risk groups),
- cabozantinib + nivolumab (Category 1 for intermediate/poor risk).
Intermediate/poor risk — ipilimumab + nivolumab (Category 1 for intermediate/poor risk) is an additional preferred option. Favorable risk — pazopanib (Category 1, TKI monotherapy option for favorable risk only). Sunitinib, cabozantinib, and pazopanib monotherapy are Category 1 options primarily for favorable risk; they are no longer recommended as initial therapy for intermediate/poor risk. TKI + CTLA-4 combinations (TKI + ipilimumab) are NOT recommended. Lenvatinib + everolimus and mTOR inhibitors are second-line options — NOT first-line.
Second-Line Treatment (After Prior IO): Cabozantinib and nivolumab are both NCCN Category 1 for subsequent treatment after prior TKI. Single-agent ipilimumab is NOT recommended. HD IL-2 has a narrow role — requires excellent performance status and organ function; major toxicity is capillary leak syndrome causing hypotension (NOT hypertension), diarrhea, and fluid overload; cardiac arrhythmias are a monitored toxicity.
TKI Monitoring: Pazopanib: monitor thyroid function (hypothyroidism occurs in 4–8% of patients). Axitinib: monitor blood pressure (hypertension occurs in up to 40% of patients). Lenvatinib: QTc prolongation can occur — correct electrolyte abnormalities (hypokalemia, hypomagnesemia) FIRST before dose reduction; if QTc remains > 480 ms after correction, dose reduce by one level.
PRACTICE QUESTIONS — RENAL CELL CARCINOMA
LL is a 51-year-old man with a 2 cm solitary renal mass (T1a) discovered incidentally after a horseback riding accident. CT chest is clear. All labs are normal. What is the most appropriate treatment option for LL's Stage I (T1a) RCC?
A. Radical nephrectomy then observation
B. Radical nephrectomy then pazopanib
C. Partial nephrectomy then observation
D. Partial nephrectomy then sunitinib
Explanation: For T1a (≤ 4 cm) tumors, partial nephrectomy is the preferred surgical approach — it preserves renal function while achieving oncologic cure. For Stage I disease, NO adjuvant systemic therapy is indicated — observation alone after surgery is the standard. Radical nephrectomy (options A and B) removes the entire kidney unnecessarily for a small 2 cm tumor; radical nephrectomy is reserved for tumors not amenable to partial resection. Adjuvant pazopanib (option B) and sunitinib (option D) are not indicated for Stage I disease — adjuvant TKI therapy has only been studied and approved for higher-risk stages.
[/expand]LL is a 51-year-old man (Stage III RCC, clear cell) who underwent radical nephrectomy for a 10 cm tumor with regional lymph node involvement. He now asks about adjuvant sunitinib. What is the most accurate response regarding the benefit of adjuvant sunitinib in LL?
- LL is likely to see his cancer recur just as quickly with adjuvant sunitinib as with no adjuvant treatment
- LL may benefit from sunitinib, but it would likely be too toxic given his comorbid hypertension
- LL is not a candidate for adjuvant sunitinib since he is not high risk for recurrence
- LL is unlikely to derive any overall survival benefit from adjuvant sunitinib
Explanation: LL has Stage III RCC with high recurrence risk, and adjuvant sunitinib is FDA-approved in this setting. However, it has been shown to improve disease-free survival (DFS) only — it has NOT demonstrated improved overall survival (OS) despite adequate follow-up. This is why sunitinib carries only a Category 3 NCCN recommendation for adjuvant use. Option A is incorrect — sunitinib DOES reduce recurrence (improves DFS). Option B is incorrect — controlled hypertension on a single agent is not a contraindication to sunitinib use; blood pressure elevation is expected but manageable. Option C is incorrect — Stage III is high-risk for recurrence, making LL a candidate.
[/expand]LL elected surveillance instead of adjuvant therapy. At 6-month follow-up, he has lymphadenopathy on abdominal CT and a 2 cm lung lesion confirmed as metastatic clear cell RCC. BP 124/72 on amlodipine. Labs: SCr 1, Ca 9.3, Hgb 11.1 g/dL, WBC/ANC/platelets normal. Karnofsky 90%. Time to recurrence < 1 year from nephrectomy. Which treatment is most appropriate for LL?
A. Axitinib + nivolumab
B. Cabozantinib + ipilimumab
C. Lenvatinib + pembrolizumab
D. Pazopanib
Explanation: LL has intermediate-risk metastatic ccRCC — time to recurrence < 1 year AND anemia (Hgb 11.1 = below normal) are IMDC risk factors. For intermediate-risk disease, Category 1 preferred regimens include lenvatinib + pembrolizumab, axitinib + pembrolizumab, cabozantinib + nivolumab, and ipilimumab + nivolumab. Among the given options, only lenvatinib + pembrolizumab (option C) is a Category 1 preferred option for intermediate risk. Cabozantinib + ipilimumab (option B) — TKI + ipilimumab combinations are NOT recommended. Pazopanib (option D) monotherapy is a Category 1 option primarily for favorable-risk disease — less preferred for intermediate risk. Axitinib + nivolumab (option A) is not an established approved combination (axitinib + pembrolizumab is the approved regimen).
[/expand]LL (same scenario) has metastatic clear cell RCC. Time to recurrence > 1 year from nephrectomy. Labs: Hgb 14.1 g/dL, SCr 1, ANC/platelets normal. Karnofsky > 80%. Which treatment is most appropriate for LL?
A. Ipilimumab + nivolumab
B. Cabozantinib
C. Lenvatinib + everolimus
D.Pazopanib
Explanation: LL has FAVORABLE-RISK metastatic ccRCC — time to recurrence > 1 year AND all IMDC parameters are normal (Hgb normal, SCr normal, ANC/platelets normal, Karnofsky > 80%). For favorable-risk disease, pazopanib is a Category 1 preferred option as TKI monotherapy. Ipilimumab + nivolumab (option A) is a preferred Category 1 option for intermediate/poor-risk disease — not the preferred choice for favorable risk. Cabozantinib (option B) is an alternative for intermediate/poor-risk patients. Lenvatinib + everolimus (option C) is a second-line option — not appropriate for first-line therapy.
[/expand]LL is scheduled to begin pazopanib 800 mg PO daily. Throughout therapy with pazopanib, LL should be monitored for which of the following?
A. Signs of depression
B. Thyroid function
C. Hyperlipidemia
D. Hyperglycemia
Answer: B. Thyroid function
Explanation: Thyroid dysfunction — particularly hypothyroidism — is an important and class-specific monitoring parameter for VEGF TKIs including pazopanib, sunitinib, and axitinib. Hypothyroidism occurs in 4–8% of patients on pazopanib and can cause fatigue, weight gain, and other symptoms that may be mistakenly attributed to cancer progression. Regular TSH monitoring is required throughout therapy. Signs of depression (option A), hyperlipidemia (option C), and hyperglycemia (option D) are not key adverse events specifically associated with VEGF TKIs in clinical trials of pazopanib.
[/expand]LL is scheduled to begin axitinib 5 mg PO BID + pembrolizumab. Throughout therapy with axitinib, LL should be monitored for which of the following?
A. Signs of depression
B. Hypertension
C. Hyperlipidemia
D. Hyperglycemia
Explanation: Hypertension is the most clinically significant and frequent adverse effect of VEGF receptor TKIs including axitinib — occurring in up to 40% of patients. Blood pressure must be monitored frequently, especially during the first months of therapy, and managed aggressively with antihypertensives to maintain target BP. Uncontrolled hypertension may require axitinib dose reduction or interruption. Depression, hyperlipidemia, and hyperglycemia are not key monitoring parameters for VEGF TKIs per KEYNOTE-426 (axitinib + pembrolizumab trial data).
[/expand]LL begins lenvatinib 20 mg daily + pembrolizumab. After grade 2 diarrhea with resulting hypokalemia in cycle 1, an ECG prior to cycle 2 reveals QTc = 510 ms. How should LL's prolonged QTc be managed?
A. Lenvatinib dose should be decreased
B. Lenvatinib should be discontinued
C. PRN 4 mg PO ondansetron should be discontinued, then repeat his ECG
D. Electrolyte abnormalities should be replaced, then repeat his ECG
Explanation: QTc prolongation with lenvatinib is often driven by electrolyte abnormalities — particularly hypokalemia and hypomagnesemia. The CORRECT first step is to replace electrolytes (potassium, magnesium) and then repeat the ECG. Per the lenvatinib prescribing information, a dose reduction is only warranted if QTc remains > 480 ms AFTER correcting electrolyte abnormalities. Lenvatinib dose reduction (option A) and discontinuation (option B) are premature before correcting the reversible cause. Ondansetron at 4 mg PO (option C) has minimal QT-prolonging effect at low doses per the prescribing information and is unlikely to be the primary driver of QTc = 510 ms; correcting electrolytes is the priority.
[/expand]LL progressed after 15 months of axitinib + pembrolizumab. He had immune-related hypothyroidism managed on levothyroxine. ECOG has declined from 0 to 1. Imaging reveals new bone metastases (2 sites). Which is an NCCN-recommended treatment option at this time?
A. Cabozantinib
B. Ipilimumab
C. High-dose interleukin-2 (HD IL-2)
D. Everolimus
Explanation: For second-line treatment of ccRCC after IO-based therapy, cabozantinib is an NCCN Category 1 recommended option — it has shown improved OS compared to everolimus in patients who progressed on prior TKI therapy. Nivolumab is also Category 1 in this setting. Single-agent ipilimumab (option B) is NOT recommended — the combination nivolumab + ipilimumab has data but single-agent ipilimumab does not. HD IL-2 (option C) is not appropriate — LL's performance status has declined to ECOG 1, and HD IL-2 requires excellent PS and organ function due to its severe toxicity profile. Everolimus (option D) is a Category 2A option in subsequent lines but is less preferred than cabozantinib or nivolumab given available OS data.
[/expand]LL is followed after partial nephrectomy for Stage I RCC. At 3-year follow-up, he has metastatic clear cell RCC with abdominal lymphadenopathy and a 2 cm lung lesion. Time to recurrence > 1 year. All labs normal. Karnofsky > 80%. Which treatment is most appropriate?
A. Temsirolimus
B. Cabozantinib
C. Lenvatinib + everolimus
D. Pazopanib
Explanation: This patient has favorable-risk metastatic ccRCC — time to recurrence > 1 year, all IMDC parameters normal (Hgb 14.1, SCr normal, ANC/platelets normal, Karnofsky > 80%). Pazopanib is a Category 1 preferred TKI option for favorable-risk first-line metastatic ccRCC. Cabozantinib (option B) is appropriate for intermediate/poor risk as first-line, or in the second-line setting. Lenvatinib + everolimus (option C) is a second-line regimen — not appropriate for first-line therapy. Temsirolimus (option A) is an mTOR inhibitor with a Category 1 recommendation for poor-risk patients — not appropriate for favorable-risk disease.
[/expand]LL progressed on pazopanib and elected HD IL-2. Which toxicity should LL be counseled about and monitored for prior to and throughout therapy?
A. Cardiac arrhythmias
B. Hypertension
C. Constipation
D. SIADH
Explanation: HD IL-2 has a broad and severe toxicity profile driven primarily by capillary leak syndrome, which causes massive fluid shifts leading to hypotension (NOT hypertension), diarrhea (NOT constipation), fluid overload, and poor urine output. Cardiac arrhythmias are a specifically monitored toxicity of HD IL-2 and must be counseled about before initiation. HD IL-2 requires administration in a closely monitored inpatient setting with highly trained staff due to its severity. Hypertension (option B) is associated with VEGF TKIs — HD IL-2 characteristically causes hypotension. Constipation (option C) is incorrect — diarrhea is the GI toxicity. SIADH (option D) is not a primary or characteristic toxicity of HD IL-2.
[/expand]A 65-year-old woman with metastatic clear cell RCC (liver and lung metastases), prior radical nephrectomy 2 years ago, ECOG 0, history of CAD and hypertension. What would you recommend next?
A. Nivolumab
B. Staged resection of liver and lung metastases
C. Cabozantinib
D. Ipilimumab + nivolumab
E. High-dose interleukin-2 (HD IL-2)
F. Cisplatin and gemcitabine
Explanation: This patient has intermediate/poor-risk metastatic ccRCC (liver metastases, time to recurrence = 2 years may be borderline, but liver metastases and tumor burden suggest intermediate/poor risk). Ipilimumab + nivolumab (CheckMate 214) is a Category 1 preferred first-line option for intermediate/poor-risk patients, demonstrating durable OS benefit with up to 35% of patients alive at 9 years. Nivolumab monotherapy (option A) is a second-line option after TKI failure — not first-line. Staged resections (option B) are not feasible for diffuse liver + lung metastases. Cabozantinib (option C) is an alternative for intermediate/poor risk but is not the strongest first-line choice here. HD IL-2 (option E) is contraindicated with CAD and hypertension. Cisplatin/gemcitabine (option F) is for urothelial carcinoma — not effective in RCC.
[/expand]Which of the following genes is NOT associated with RCC?
[expand] Answer: C. RB (Retinoblastoma gene)Explanation: RB is primarily linked to retinoblastoma and osteosarcoma — it is NOT classically associated with renal cell carcinoma. VHL (option A) mutations are found in clear cell RCC and Von Hippel-Lindau disease — the most common hereditary cause of ccRCC. mTOR (option B) pathway mutations are seen in chromophobe RCC and tuberous sclerosis complex-associated RCC, and mTOR inhibitors are a treatment class for RCC. FLCN (option D) encodes folliculin — mutations cause Birt-Hogg-Dubé syndrome, which predisposes to chromophobe RCC, oncocytomas, spontaneous pneumothoraces, and skin fibrofolliculomas.
[/expand]A 51-year-old man with recurrent spontaneous pneumothoraces, bilateral pleurodesis history, right upper lobectomy at age 22, and family history of emphysema and pneumothorax, undergoes right radical nephrectomy for a 3 cm mass revealing chromophobe RCC. Which gene mutation is associated with this patient's condition?
A. MET
B. FH
C. Succinate dehydrogenase
D. FLCN
E. HBB
Explanation: The clinical triad of chromophobe RCC + spontaneous pneumothoraces + family history of pneumothorax and lung cysts is the classic presentation of Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the FLCN (folliculin) gene. This autosomal dominant syndrome also presents with skin fibrofolliculomas. MET (option A) mutations cause hereditary papillary RCC — not chromophobe. FH (option B) fumarate hydratase mutations cause hereditary leiomyomatosis and RCC (HLRCC) — a highly aggressive papillary subtype. Succinate dehydrogenase (option C) mutations cause SDH-deficient RCC — typically aggressive and not the chromophobe subtype. HBB (option E) is a hemoglobin gene associated with sickle cell disease — no connection to RCC.
[/expand]SECTION 3: TESTICULAR CANCER
CONCEPTUAL SUMMARY
Epidemiology: Most common solid tumor in males aged 15–35 years. Highly curable even in advanced stages due to platinum sensitivity.
Histologic subtypes:
- Germ cell tumors (GCTs) account for ~95% of cases.
- Seminoma: slower-growing, very radio and chemosensitive, typically presents in 30s–40s.
- Non-seminoma (NSGCT): faster-growing, includes embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma. ANY non-seminomatous component (even < 5%) classifies the tumor as a NONSEMINOMA for treatment purposes.
Tumor Markers:
- AFP — only elevated in NSGCT; NEVER elevated in pure seminoma (elevated AFP excludes pure seminoma).
- β-hCG — elevated in both NSGCT and ~15% of pure seminomas.
- LDH — non-specific, correlates with tumor burden.
IGCCCG Risk Stratification:
For NONSEMINOMA
- Good risk: testicular/retroperitoneal primary, no non-pulmonary visceral metastases (pulmonary mets = OK), AFP < 1,000, β-hCG < 5,000, LDH < 1.5× ULN.
- Intermediate risk: same primary and metastasis criteria + AFP 1,000–10,000 or β-hCG 5,000–50,000 or LDH 1.5–10× ULN.
- Poor risk: mediastinal primary OR non-pulmonary visceral metastases (brain, bone, liver) OR AFP > 10,000 or β-hCG > 50,000 or LDH > 10× ULN.
For SEMINOMA
- Good risk: any AFP normal + no non-pulmonary visceral metastases.
- Intermediate risk: non-pulmonary visceral metastases. There is NO poor-risk category for pure seminoma.
Treatment:
Surgery (radical inguinal orchiectomy) is the first step for all stages.
- Good-risk disease: BEP × 3 cycles (preferred) or EP × 4 cycles (if bleomycin contraindicated).
- Intermediate/poor-risk disease: BEP × 4 cycles or VIP × 4 cycles (if bleomycin unsuitable). Carboplatin does NOT replace cisplatin in curative-intent regimens (inferior in relapse-free survival).
- BEP regimen: bleomycin 30 units IV weekly, etoposide 100 mg/m² days 1–5, cisplatin 20 mg/m² days 1–5, q21 days.
Stage I Nonseminoma (Clinical): After radical orchiectomy — options include active surveillance, retroperitoneal lymph node dissection (RPLND), or adjuvant BEP × 1–2 cycles depending on risk features (LVI, spermatic cord involvement). Stage IIA/IIB NSGCT with normal markers: primary RPLND (bilateral nerve-sparing) is the standard — chemotherapy is reserved for bulky (Stage IIC/III) or marker-positive disease. Stage II Seminoma: options include radiation (traditional), BEP × 3–4 cycles, or primary RPLND in select centers.
Bleomycin Toxicity: Pulmonary toxicity is cumulative-dose related (risk increases > 400 units total). Risk factors: age > 40, renal impairment, cumulative dose > 400 units, concomitant thoracic radiation, tobacco use. Monitor: baseline PFTs (DLCO), monitor for dyspnea, dry cough, crackles. G-CSF use with bleomycin: association with increased pulmonary toxicity in Hodgkin lymphoma — this risk is NOT proven in testicular cancer. G-CSF MAY still be used when clinically necessary in patients receiving BEP.
Cisplatin Long-Term Toxicities: Peripheral neuropathy (up to 40%), ototoxicity (1 in 5 survivors), nephrotoxicity, cardiovascular disease (3–7-fold increased risk), secondary malignancies (1.7-fold increased risk). BEP survivors: monitored for secondary malignancies (GI cancers, leukemia) and cardiovascular disease — these are the leading causes of premature mortality in testicular cancer survivors.
Supportive Care: Pre-cisplatin hydration with NS ± mannitol. Triple antiemetics (NK1 + 5-HT3 + dexamethasone). Fertility preservation: sperm banking BEFORE starting any chemotherapy — all men should be offered this. Avoid high-flow supplemental oxygen in bleomycin-treated patients undergoing anesthesia (risk of pulmonary toxicity).
PRACTICE QUESTIONS — TESTICULAR CANCER
SD is a 26-year-old male with embryonal cell carcinoma (NSGCT) with retroperitoneal lymphadenopathy and pulmonary nodules. Post-orchiectomy markers: AFP 500 ng/mL, β-hCG 3,000 IU/mL, LDH 290 IU/L (ULN = 250). What is SD's risk classification?
A. Good risk
B. Intermediate risk
C. Poor risk
D. Unable to determine
Explanation: SD has nonseminomatous GCT (embryonal carcinoma) with a testicular primary, retroperitoneal lymphadenopathy, and pulmonary metastases only (no non-pulmonary visceral metastases). For good-risk NSGCT: testicular/retroperitoneal primary + no non-pulmonary visceral metastases + AFP < 1,000 (SD's AFP = 500 ✓) + β-hCG < 5,000 (SD's β-hCG = 3,000 ✓) + LDH < 1.5× ULN (SD's LDH = 290; ULN = 250; ratio = 1.16× ULN ✓). All criteria for good risk are met. Pulmonary metastases are allowed under good-risk classification — only non-pulmonary visceral metastases (brain, bone, liver) would confer poor risk.
[/expand]SD has stage IIIA nonseminoma, good-risk testicular cancer and will start BEP × 3 cycles. He asks about filgrastim (G-CSF) use. Which of the following best explains the use of filgrastim with BEP?
- G-CSF with bleomycin has been associated with increased risk of bleomycin-induced pulmonary toxicity in patients receiving BEP and is contraindicated
- BEP is associated with a high (> 20%) incidence of febrile neutropenia, so G-CSF primary prophylaxis is recommended in all patients
- Since SD has metastatic cancer, the goal of therapy is palliative — G-CSF should only be used if SD develops febrile neutropenia during cycle 1
- G-CSF may increase one's risk of bleomycin-induced pulmonary toxicity, but this risk is not proven and G-CSF may still be used when necessary in patients receiving BEP
Explanation: Bleomycin pulmonary toxicity (BPT) has been associated with G-CSF use in Hodgkin lymphoma — but in testicular cancer, no increased risk has been definitively proven with G-CSF in BEP regimens. G-CSF may still be used for primary prophylaxis in high-risk patients or as secondary prophylaxis. Option A is incorrect — G-CSF is not contraindicated with BEP; the concern exists but is unproven in this context. Option B is incorrect — BEP is associated with intermediate (10–20%) febrile neutropenia risk, not high (> 20%); primary prophylaxis is risk-based. Option C is incorrect — SD's disease is treated with curative intent, not palliatively.
[/expand]SD completed 3 cycles of BEP and has no evidence of disease. He is now being followed for survivorship. Which survivorship issues is SD at risk for?
A. Secondary malignancies and cardiovascular disease
B. Ocular toxicity and cardiovascular disease
C. Ocular and dermatologic toxicity
D. Pulmonary toxicity and hepatotoxicity
Answer: A. Secondary malignancies and cardiovascular disease
Explanation: Testicular cancer survivors treated with BEP (cisplatin + etoposide + bleomycin) face a 1.7-fold increased risk of secondary malignant neoplasms (particularly GI cancers and leukemia from etoposide exposure) and a 3–7-fold increased cardiovascular disease risk (from cisplatin's endothelial effects and platinum accumulation). These are the leading causes of premature mortality in testicular cancer survivors. Pulmonary toxicity from bleomycin is a known long-term risk, but hepatotoxicity (option D) is not strongly associated with BEP therapy. Ocular toxicity and dermatologic toxicity (options B and C) are not hallmark long-term complications of BEP-based therapy.
[/expand]A 28-year-old man with pure seminoma (lung metastasis, no other organ involvement) presents 4 weeks after orchiectomy. AFP, β-hCG, and LDH are pending. How would you characterize his risk of recurrence?
A. Good risk
B. Intermediate risk
C. Poor risk
D. Need to know tumor markers prior to discussing risk
Explanation: This patient has pure seminoma with only pulmonary metastases (no non-pulmonary visceral metastases). For pure seminoma, the IGCCCG risk system is simpler: Good risk = any β-hCG or LDH + normal AFP + no non-pulmonary visceral metastases. Lung metastases are allowed under good-risk seminoma. Intermediate risk for seminoma requires non-pulmonary visceral metastases (liver, bone, brain). There is NO poor-risk category for pure seminoma. AFP is always normal in pure seminoma — elevated AFP would reclassify the tumor as having non-seminomatous elements. Since the histology is confirmed pure seminoma and metastases are pulmonary only, good risk is the correct classification even before marker results return.
[/expand]A 56-year-old active smoker with COPD has a 7 × 5.5 cm anterior mediastinal mass. Biopsy confirms pure yolk sac tumor. AFP = 8,941 ng/mL, LDH = 273, β-hCG undetectable. Testicular ultrasound is negative. What is the most appropriate initial treatment?
A. Resection of the mediastinal mass
B. Four cycles of BEP (bleomycin/etoposide/cisplatin) chemotherapy
C. Four cycles of VIP (etoposide/ifosfamide/cisplatin) chemotherapy
D. Four cycles of EP (etoposide/cisplatin) chemotherapy
Explanation: This patient has a primary mediastinal NSGCT (yolk sac tumor, AFP = 8,941) — a mediastinal primary automatically classifies as POOR RISK in the IGCCCG system regardless of markers. For poor-risk disease, 4 cycles of BEP is the standard first-line chemotherapy. Despite COPD, BEP × 4 is still the standard — VIP (option C) would be appropriate if bleomycin is truly contraindicated (e.g., very severe pulmonary impairment), but the question doesn't indicate bleomycin is contraindicated. Resection alone (option A) is not appropriate as initial treatment for metastatic NSGCT — chemotherapy must precede surgery. EP × 4 (option D) is for good-risk disease when bleomycin is contraindicated — not standard for poor-risk.
[/expand]A 28-year-old man has a mixed germ cell tumor (95% seminoma, 5% embryonal carcinoma), Stage IIB (2.5 cm para-aortic lymph nodes), lymphovascular invasion, spermatic cord involvement. All tumor markers are normal pre- and post-orchiectomy. What is the diagnosis and next step in treatment?
A. Seminoma; Surveillance
B. Seminoma; Radiation to ipsilateral iliac and para-aortic lymph nodes
C. Nonseminoma; 1–2 cycles of BEP chemotherapy
D. Nonseminoma; Bilateral nerve-sparing retroperitoneal lymph node dissection (RPLND)
Explanation: Despite the tumor being predominantly seminoma (95%), the presence of ANY non-seminomatous component (embryonal carcinoma 5%) classifies the tumor as a NONSEMINOMA for all treatment decisions. For clinical Stage IIA/IIB NSGCT with NORMAL tumor markers, primary RPLND (bilateral nerve-sparing technique to preserve ejaculatory function) is the standard of care — it provides definitive pathologic staging and treatment. Chemotherapy (option C) is reserved for bulky Stage IIC or marker-positive NSGCT. Options A and B treat this as a seminoma, which is incorrect given the mixed histology. RPLND may be followed by adjuvant chemotherapy depending on the extent of lymph node involvement found pathologically.
[/expand]22. DJ is a 60-year-old male who is being started on sunitinib as first-line therapy for metastatic renal cell carcinoma. Which of the following lists the appropriate monitoring parameters for this drug?
- A. Blood pressure, liver function tests, EKG, pulmonary function test (12%)
- B. WBC, platelets, blood pressure, thyroid function, infusion reactions, skin changes (21%)
- C. Blood pressure, liver function tests, skin changes, pulmonary function test (22%)
- D. WBC, platelets, blood pressure, liver function tests, signs of bleeding, skin changes (45%)
- Sunitinib is an oral multikinase inhibitor that limits tumor growth by targeting angiogenesis via inhibition of a variety of kinases such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor. FMS-like tyrosine kinase-3 (FLT3), colony-stimulating factor type 1 (CSF-1R), and c-kit. As a VEGFR inhibitor, sunitinib can lead to hypertension.
- Furthermore, it has a black box warning for hepatotoxicity, and liver function tests should be monitored during therapy. Other side effects include neutropenia, thrombocytopenia, QTc prolongation, hemorrhagic events, thyroid dysfunction, and changes in skin or hair color.
- Infusion reactions and pulmonary function tests are not concerns with sunitinib.
- Complete blood count and platelets. blood pressure, liver function tests, thyroid function, signs of bleeding, and skin changes should all be monitored with sunitinib.
- Sunitinib can lead to yellow discoloration of the skin and also hair depigmentation (occurs after 5-6 weeks of treatment but can be reversed as early as 2-3 weeks after treatment is discontinued), which is thought to be caused by its inhibition of c-kit signaling.
24. Ifosfamide is known to produce which of the following adverse effects in a male patient being treated for testicular cancer?
- A. Red cell aplasia (6%)
- B. Conjunctivitis (3%)
- C. Pulmonary fibrosis (7%)
- D. Hemorrhagic cystitis (85%)
- Ifosfamide (ifex) is converted to the urotoxic metabolite, acrolein, which can bind to the bladder wall and produce hemorrhagic cystitis.
- Cyclophosphamide is another alkylating agent that is also known to form acrolein and cause this same adverse reaction.
- Mesna is recommended to be given around the time of ifosfamide administration to prevent this adverse effect. It is usually given at the same time as ifosfamide in a dose specific to the dose of ifosfamide.
58. AZ has failed multiple therapies for metastatic renal cell cancer. His oncologist decided to treat him with temsirolimus. Which of the following are the most common adverse effects of temsirolimus?
- A. Peripheral edema and hypercholesterolemia (62%)
- B. Capillary-leak syndrome and hypotension (13%)
- C. Diarrhea and hand-foot syndrome (11%)
- D. Hypertension and proteinuria (14%)
- Peripheral edema and hypercholesterolemia are common side effects of temsirolimus therapy, making the first answer choice correct.
- Capillary-leak syndrome and hypotension (second answer choice) are significant concerns of IL-2 therapy.
- Diarrhea is also commonly associated with temsirolimus, but not a hand-foot syndrome (third answer choice).
- Hypertension and proteinuria (last answer choice) most commonly occur with bevacizumab therapy.
- Hyperglycemia, hyperlipidemia, peripheral edema, and diarrhea are common side effects associated with temsirolimus.
- Temsirolimus-induced hypercholesterolemia and hyperglycemia are caused by the inhibition of the mammalian target of rapamycin (mTOR)-regulated metabolism of glucose and cholesterol.
77. CG is a 58-year-old male with metastatic renal cell carcinoma, and the team decides to start him on pazopanib. Which of the following receptors does pazopanib NOT target?
- A Platelet-derived growth factor receptor (17%)
- B Vascular endothelial growth factor receptor (VEGFR) (11%)
- C Epidermal growth factor receptor (EGFR) (39%)
- D c-Kit (33%)
- Pazopanib (Votrient) is a multikinase inhibitor that limits tumor growth by targeting angiogenesis via inhibition of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and c-kit.
- It does not inhibit the epidermal growth factor receptor (EGFR).
- Pazopanib (Votrient) inhibits angiogenesis by targeting VEGFR, platelet-derived growth factor receptor, and c-kit.
- Drugs that inhibit VEGFR (such as bevacizumab, ramucirumab, sorafenib, sunitinib, and pazopanib) are commonly associated with hypertension. Blood pressure should be monitoring during therapy.
- Generic and brand names: Sunitinib (Sutent), Pazopanib (Votrient), Ramucirumab (Cyramza).
95. Which of the medications does not have FDA approval for the treatment of renal cell carcinoma?
[expand] Answer (D)- In order to exhibit activity for renal cell carcinoma, the agent must possess activity against platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).
- These two, among other growth factors, are important for clear cell renal cell carcinoma growth and metastases. The use of multitargeted agents such as sorafenib, sunitinib, and pazopanib all target PDGFR and VEGFR.
- Erlotinib only targets epidermal growth factor receptor (EGFR) and therefore is inactive against renal cell carcinoma.
102. DK will be receiving sunitinib for the new diagnosis of metastatic renal cell cancer. Which one of the following recommendations is best to maximize the safety and efficacy of his sunitinib therapy?
- A. Give pyridoxine daily to prevent sunitinib-induced hand-foot skin reaction (24%)
- B. Give sunitinib twice daily to maximize efficacy (8%)
- C. Monitor cholesterol concentrations at baseline and then at regular intervals (13%)
- D. Monitor thyroid function tests at baseline and then at regular intervals (54%)
- The last answer choice is the best recommendation. Several retrospective analyses found that 45% to 85% of the patients treated with these agents have abnormal thyroid function tests. Of these patients, up to 26% required thyroid hormone replacement.
- Pyridoxine (first answer choice) has been used to treat capecitabine-induced hand-foot syndrome based on a few case reports. Its use for the prevention of hand-foot syndrome is questionable because there is inadequate evidence to show any benefit of pyridoxine treatment of this condition compared with placebo.
- The recommended dose for sunitinib (second answer choice) in RCC is 50 mg orally once daily for four weeks on and then two weeks off for each cycle. Hypercholesterolemia (third answer choice) is a major concern with temsirolimus but not sunitinib, making this answer incorrect.
- Patients receiving sunitinib may develop subclinical or clinical hypothyroidism and subsequently require thyroid hormone replacement.
- The mechanism of sunitinib-induced hypothyroidism is unknown. However, sunitinib may have a direct effect on the thyroid through inhibition of VEGFR and/or PDGFR. It may also inhibit thyroid peroxidase activity, which reduces the synthesis of the thyroid hormones.
111. TK is a 56-year-old man with metastatic renal cell cancer (RCC) who was initiated on sorafenib 400 mg orally twice daily. Six weeks into treatment, he developed severe diarrhea (7 stools/day). He was asked to discontinue sorafenib, and the reaction resolved one week later. Based on this information, which one of the following is the best action to take at this time?
- A. Discontinue sorafenib and initiate sunitinib (21%)
- B. Discontinue sorafenib and initiate bevacizumab (13%)
- C. Reinitiate sorafenib 400 mg orally twice daily (8%)
- D. Decrease sorafenib to 400 mg orally once daily (58%)
- The last answer choice is the best answer. Per the Common Terminology Criteria for Adverse Events (CTCAE), TK has grade 3 GI toxicity. Typically, grade ≥ 3 toxicities require dose interruptions and/or dose adjustments.
- Based on the Treatment Approaches in RCC Global Evaluation Trial (TARGET), the initial dosage reduction from sorafenib 400 mg twice daily when resuming sorafenib should be sorafenib 400 mg/day and then 400 mg every other day. Similar dose modification guidelines can be found in sorafenib’s package insert for dermatologic toxicities when used in hepatocellular or RCC.
- Sorafenib, at the same dose, (third answer choice) may put the patient at the same or increased risk of another episode of severe diarrhea.
- Sorafenib discontinuation (first and second answer choices) may alleviate the risk of diarrhea, but the patient will miss the opportunity to benefit from sorafenib.
- Dose interruptions and/or dose reductions of sorafenib are based on the grade of the toxicity.
- Diarrhea, rash, fatigue, and hand-foot skin reactions are the most common toxicities associated with sorafenib.
122. QC was initially receiving temsirolimus 20 mg intravenously once every week for his RCC. After eight weeks on the above dose of temsirolimus, he had several blood glucose concentrations greater than 330 mg/dL. Several interventions to control high blood glucose failed, and his temsirolimus was placed on hold. Now that his blood glucose levels have normalized, his physician would like to restart temsirolimus. Which of the following is the most appropriate dose of temsirolimus to restart QC on?
- A 25 mg intravenously once every week (8%)
- B 25 mg intravenously once every 2 weeks (18%)
- C 15 mg intravenously once every week (53%)
- D 20 mg intravenously once every 2 weeks (21%)
- The recommended dosage adjustment for temsirolimus in the setting of CTCAE grade 3 or greater adverse events is to hold until toxicities have resolved to grade 2 or less. Temsirolimus should be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week. Because the patient was taking 20 mg/week, the next dosage adjustment should be 15 mg/week (third answer choice).
- Restarting at the original dose of 25 mg/week (first answer choice) is not recommended.
- Extending the dosing interval longer than one week (second and fourth answer choices), thereby lowering the average weekly dose, is not recommended.
- Temsirolimus should be held for ANC <1000/mm³, platelets < 75,000/mm³ or CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, temsirolimus may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week.
- Temsirolimus is a CYP3A4 substrate, and strong CYP3A4 inducers or inhibitors affect its clearance. Thus, appropriate dose adjustments for temsirolimus should be considered when given concomitantly with these agents.