Quick Medical Diagnosis & Treatment 2021

Renal Cell Carcinoma

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For further information, see CMDT Part 39-20: Renal Cell Carcinoma

Key Features

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Essentials of Diagnosis

Gross or microscopic hematuria
Flank pain or mass in some patients
Systemic symptoms such as fever, weight loss may be prominent
Solid renal mass on imaging

General Considerations

~2.6% of all adult cancers
In 2019 in the United States, it is estimated that approximately 73,820 cases of renal cell carcinoma will be diagnosed and 14,770 deaths will result

Demographics

Peak incidence in sixth decade of life
Male-to-female ratio = 2:1
Risk factors: physical inactivity, obesity, and diabetes mellitus
Cigarette smoking is the only known significant environmental risk factor
Familial: von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma, hereditary leiomyoma-renal cell carcinoma, Birt-Hogg-Dube syndrome
Association: dialysis-related acquired cystic disease

Clinical Findings

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Symptoms and Signs

Hematuria (gross or microscopic) in 60% of cases
Flank pain or an abdominal mass in ~30%
Triad of flank pain, hematuria, and mass in ~10–15%, often a sign of advanced disease
Fever occurs as a paraneoplastic symptom
Symptoms of metastatic disease (cough, bone pain) in ~20–30% at presentation
Often detected incidentally

Differential Diagnosis

Angiomyolipomas (fat density usually visible by CT)
Renal pelvis urothelial cancers (more central location, involvement of the collecting system, positive urinary cytology)
Renal oncocytomas (indistinguishable from renal cell carcinoma preoperatively)
Renal abscesses
Adrenal tumors (superoanterior to the kidney)

Diagnosis

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Laboratory Tests

Hematuria in 50%
Paraneoplastic syndromes
- Erythrocytosis from increased erythropoietin production in ~5% (but anemia is far more common)
- Hypercalcemia in 10%
- Stauffer syndrome, a reversible syndrome of hepatic dysfunction

Imaging Studies

Solid renal masses on abdominal ultrasonography or CT
CT and MRI scanning are the most valuable imaging tests; they confirm character of the mass, stage the lesion
Chest radiographs for pulmonary metastases
Bone scans for large tumors, bone pain, elevated alkaline phosphatase levels
Brain imaging should be obtained in patients with high metastatic burden or in those with neurologic deficits

Treatment

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Medications

For metastatic renal cell carcinoma, no effective cytotoxic chemotherapy is available
Vinblastine yields short-term partial response rates of 15%
Bevacizumab can prolong time to progression in persons with metastatic disease (Table 39–2)
Cytokine-based immunotherapies, such as interferon-alpha and interleukin-2 produced partial response rates of 15–20% and 15–35%, respectively
Vascular endothelial growth factor (VEGF) and Raf-kinase inhibitors: oral agents, well-tolerated, with demonstrated effectiveness in patients with advanced kidney cancer, especially clear cell carcinoma (~40–60% response rate); agents include
- Sunitinib
- Pazopanib
- Cabozantanib
- Axitinib
- Sorafanib
Sunitinib has been approved for adjuvant use after complete surgical resection in patients with adverse pathological features
Everolimus and temsirolimus are approved for use in patients with prior anti-VEGF therapy as is the combination of lenvatinib plus everolimus
Nivolumab is approved for the treatment of patients with metastatic disease who have progressed on antiangiogenic therapy
Nivolumab in combination with the anti-CTLA4 immunotherapy ipilumab and pembrolizumab in combination with the VEGF inhibitor axitinib
- Have proved superior to sunitinib in previously untreated intermediate- and poor-risk metastatic clear cell renal cell carcinoma
- Are considered the standard first-line treatment for this patient population

Table 39–2.Treatment choices for cancers responsive to systemic agents.

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Table 39–2. Treatment choices for cancers responsive to systemic agents.

Diagnosis

Initial Treatment

Acute lymphoblastic leukemia (ALL)

Induction combination chemotherapy (Philadelphia chromosome-positive): Cyclophosphamide, vincristine, doxorubicin/daunorubicin, dexamethasone (hyper-CVAD) alternating with cytarabine, methotrexate; add imatinib or dasatinib or nilotinib

Induction combination chemotherapy (Philadelphia chromosome–negative): Daunorubicin, vincristine, prednisone, pegaspargase, cyclophosphamide; or hyper-CVAD) alternating with methotrexate and cytarabine

Maintenance chemotherapy: Methotrexate, 6-mercaptopurine, vincristine, prednisone

Acute myeloid leukemia (AML)

Induction combination chemotherapy:

Cytarabine with daunorubicin or idarubicin,

with gemtuzumab ozogamicin (CD33-positive), or
with midostaurin (FLT3-mutated), or
with cladribine, or
with fludarabine

Alternative chemotherapy for ≥ 60 years old:

Azacitidine, decitabine, or low-dose cytarabine with or without venetoclax; or

Glasdegib plus cytarabine; or

Ivosidenib (IDH1 mutation); or

Enasidenib (IDH2 mutation)

Chronic myeloid leukemia (CML)

Nilotinib or Dasatinib or Imatinib or Bosutinib

Chronic lymphocytic leukemia (CLL)

Combination chemotherapy: Venetoclax, obinutuzumab

Single-agent chemotherapy: Ibrutinib

Hairy cell leukemia

Cladribine or pentostatin

Hodgkin lymphoma

Combination chemotherapy: Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD), or

Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP)

Non-Hodgkin lymphoma (intermediate and high grade)

Combination chemotherapy: Cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab (CHOP-R), or

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (dose-adjusted R-EPOCH) (for double-/triple-hit)

Non-Hodgkin lymphoma (low grade)

Combination chemotherapy:

Bendamustine plus obinutuzumab or rituximab, or

Cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab (CHOP-R), or

Cyclophosphamide, vincristine, prednisone, rituximab (CVP-R), or

Lenalidomide, rituximab

Plasma cell myeloma

Combination chemotherapy (transplant candidates):

Bortezomib, dexamethasone, cyclophosphamide, or

Bortezomib, dexamethasone, lenalidomide

Followed by autologous or mini-allogeneic stem cell transplantation

Combination chemotherapy (non-transplant candidates):

Bortezomib, lenalidomide, dexamethasone, or

Daratumumab, lenalidomide, dexamethasone, or

Lenalidomide, dexamethasone, or

Bortezomib, cyclophosphamide, dexamethasone

Waldenström macroglobulinemia

Plasmapheresis alone or followed by combination chemotherapy:

Bortezomib, dexamethasone, rituximab, or

Cyclophosphamide, dexamethasone, rituximab, or

Bendamustine, rituximab

Polycythemia vera

Phlebotomy or hydroxyurea or aspirin

Non–small cell lung cancer

Combination chemotherapy:

Cisplatin, vinorelbine, or

Cisplatin, etoposide, or

Paclitaxel, carboplatin, or

Cisplatin, gemcitabine or docetaxel (squamous histology), or

Cisplatin, pemetrexed (nonsquamous histology), or

Carboplatin, albumin-bound paclitaxel, or

Dabrafenib/trametinib (BRAF V600F mutation), or

Pembrolizumab; carboplatin or cisplatin/pemetrexed/pembrolizumab (nonsquamous); carboplatin/paclitaxel/bevacizumab/atezolizumab (nonsquamous); carboplatin/paclitaxel or albumin-bound paclitaxel/pembrolizumab (squamous) (PD-L1 expression)

Single-agent chemotherapy:

Erlotinib, gefitinib, osimertinib, afatinib or dacomitinib (EGFR mutation positive)

Crizotinib, alectinib, ceritinib, or brigatinib (ALK mutation positive)

Ceritinib, crizotinib, or entrectinib (ROS1 rearrangement)

Larotrectinib or entrectinib (NTRK gene fusion positive)

Small cell lung cancer

Combination chemotherapy:

Cisplatin, etoposide, or

Carboplatin, etoposide, or

Carboplatin, etoposide, atezolizumab

Mesothelioma

Combination chemotherapy:

Cisplatin or carboplatin, pemetrexed, with or without bevacizumab or

Gemcitabine, cisplatin

Single-agent chemotherapy: Pemetrexed or vinorelbine

Head and neck cancer

Combination chemotherapy:

Cisplatin, 5-fluorouracil, or

Paclitaxel, carboplatin, or

Docetaxel, cisplatin, 5-fluorouracil, or

Cisplatin or cetuximab with radiation therapy, or

Cisplatin or carboplatin/5-fluorouracil/cetuximab, or

Pembrolizumab (PD-L1 expression), or

Pembrolizumab/cisplatin or carboplatin/5-fluorouracil

Esophageal and esophagogastric junction cancer

Combination chemotherapy: Cisplatin, 5-fluorouracil or capecitabine, or

Paclitaxel, carboplatin, or

Oxaliplatin, 5-fluorouracil or capecitabine, or

Add trastuzumab for HER2-overexpressing metastatic adenocarcinoma

Uterine cancer

Hormone therapy: Progestins, tamoxifen, aromatase inhibitors, or fulvestrant, or

Combination chemotherapy:

Carboplatin, paclitaxel

Carboplatin, paclitaxel, trastuzumab (HER2 positive)

Ovarian cancer

Combination chemotherapy:

Paclitaxel, carboplatin with or without bevacizumab, or

Carboplatin, liposomal doxorubicin, or

Docetaxel, carboplatin, or

Paclitaxel, cisplatin

Cervical cancer

With radiation: Cisplatin or carboplatin

Combination chemotherapy:

Cisplatin or carboplatin, paclitaxel with or without bevacizumab, or

Cisplatin, topotecan, or

Topotecan, paclitaxel with or without bevacizumab

Breast cancer

Adjuvant hormone therapy: Premenopausal: Tamoxifen

Postmenopausal: Aromatase inhibitors (anastrozole, letrozole, exemestane)

Adjuvant chemotherapy (without trastuzumab):

Doxorubicin, cyclophosphamide, paclitaxel, or

Docetaxel, cyclophosphamide

Adjuvant chemotherapy (HER2 positive):

Doxorubicin, cyclophosphamide, paclitaxel, trastuzumab with or without pertuzumab, or

Docetaxel, carboplatin, trastuzumab with or without pertuzumab or

Paclitaxel plus trastuzumab

Choriocarcinoma (trophoblastic neoplasms)

Single-agent chemotherapy: Methotrexate or dactinomycin for low-risk disease

Combination chemotherapy: Etoposide, methotrexate, dactinomycin, cyclophosphamide, vincristine (EMA-CO) for high-risk disease

Testicular cancer

Combination chemotherapy: Cisplatin, etoposide (EP), or

Bleomycin, etoposide, cisplatin (BEP), or

Etoposide, mesna, ifosfamide, cisplatin (VIP)

Kidney (renal cell) cancer

Clear cell histology:

Axitinib plus pembrolizumab, ipilimumab plus nivolumab, pazopanib, sunitinib, or cabozantinib

Non–clear cell histology: Sunitinib

Bladder cancer

Combination chemotherapy: Gemcitabine, cisplatin, or

Methotrexate, vinblastine, doxorubicin, cisplatin (MVAC), or

Atezolizumab, pembrolizumab, or gemcitabine plus carboplatin (cisplatin ineligible)

Prostate cancer

Hormone therapy: Luteinizing hormone–releasing agonist (leuprolide, goserelin, triptorelin, histrelin), or degarelix with or without an antiandrogen (flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide) or abiraterone

Chemotherapy: Docetaxel, prednisone, cabazitaxel

Brain cancer (anaplastic astrocytoma and glioblastoma multiforme)

Single-agent chemotherapy with radiation therapy: Temozolomide

Neuroblastoma

Combination chemotherapy: Cyclophosphamide, doxorubicin, cisplatin, etoposide

Thyroid cancer

Single-agent chemotherapy: Radioiodine (¹³¹I) or sorafenib, lenvatinib, vandetanib (medullary thyroid cancer) or cabozantinib (medullary thyroid cancer)

Combination chemotherapy: Paclitaxel/carboplatin or docetaxel/doxorubicin (anaplastic carcinoma)

Adrenal cancer

Mitotane

Stomach (gastric) cancer

Combination chemotherapy:

5-Fluorouracil, leucovorin, oxaliplatin, docetaxel (perioperative)

5-Fluorouracil or capecitabine oxaliplatin or cisplatin or paclitaxel

Trastuzumab added for HER2-overexpressing adenocarcinomas

Pancreatic cancer

Combination chemotherapy:

Gemcitabine, nab-paclitaxel, or

5-Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or

Gemcitabine, capecitabine, or

Gemcitabine, cisplatin (for BRCA1/2 or PALB2 mutation)

Single-agent chemotherapy: Gemcitabine, capecitabine, or 5-fluorouracil

Colon cancer

Combination chemotherapy:

5-Fluorouracil, leucovorin, oxaliplatin (FOLFOX) with or without bevacizumab, or

Capecitabine, oxaliplatin (CapeOx) with or without bevacizumab, or

5-Fluorouracil, leucovorin, irinotecan (FOLFIRI) with or without bevacizumab

Cetuximab or panitumumab added to FOLFOX or FOLFIRI for KRAS/NRAS/BRAF wild-type and left-sided tumors

Single-agent chemotherapy: Capecitabine or 5-fluorouracil/leucovorin

Rectal cancer

Chemotherapy with radiation: 5-Fluorouracil or capecitabine

For adjuvant treatment, same regimens used with colon cancer

Anal cancer

Combination chemotherapy with radiation: 5-Fluorouracil or capecitabine with mitomycin

Carcinoid

Octreotide LAR with or without telotristat or lanreotide, or everolimus

Osteosarcoma

Combination chemotherapy: Cisplatin, doxorubicin, or

Methotrexate, doxorubicin, cisplatin (MAP)

Soft tissue sarcomas

Combination chemotherapy:

Doxorubicin, dacarbazine (AD), or

Doxorubicin, ifosfamide, mesna (AIM), or

Mesna, doxorubicin, ifosfamide, dacarbazine (MAID), or

Ifosfamide, epirubicin, mesna, or

Gemcitabine and docetaxel, vinorelbine, or dacarbazine

Single-agent chemotherapy: Imatinib or sunitinib or regorafenib (gastrointestinal stromal tumors)

Melanoma

Pembrolizumab, nivolumab or nivolumab/ipilimumab (non-BRAF mutation)

Combination chemotherapy: (BRAF mutation): Dabrafenib/trametinib or vemurafenib/cobimetinib or encorafenib/binimetinib

Single-agent chemotherapy: (BRAF mutation): Vemurafenib or dabrafenib

Hepatocellular cancer

Sorafenib or lenvatinib

Kaposi sarcoma

Liposomal doxorubicin or paclitaxel

Surgery

Surgical extirpation for localized renal cell carcinoma
Partial nephrectomy for patients with a small cancer, single kidney, bilateral lesions, or significant medical kidney disease
Radical nephrectomy is indicated in cases of larger tumors (> 7 cm) and those where partial nephrectomy is not technically feasible
Cytoreductive nephrectomy remains an option in select patients with intermediate risk disease

Therapeutic Procedures

Cell type and histologic pattern do not affect treatment
Surveillance in selected patients may be warranted, and percutaneous biopsy can provide information regarding histology and grade to help inform the decision
Patients with metastatic disease usually should be considered for palliative surgery followed by systemic therapy with biologic response modifiers

Outcome

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Prognosis

Tumors confined to the renal capsule (T1–T2) demonstrate 5-year disease-free survivals of 90–100% after radical nephrectomy
Tumors extending beyond the renal capsule (T3 or T4) and node-positive tumors have 50–60% and 0–15% 5-year disease-free survival, respectively
For patients with solitary resectable metastases, radical nephrectomy with resection of the metastasis has resulted in 5-year disease-free survival rates of 15–30%

When to Refer

Refer patients with solid renal masses or complex cysts to a urologist for further evaluation
Refer patients with renal cell carcinoma to a urologic surgeon for surgical excision
Refer patients with metastatic disease to an oncologist

References

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Dey S et al. Neoadjuvant targeted molecular therapy before renal surgery. Urol Clin North Am. 2017 May;44(2):289–303.
[PubMed: 28411920]

Haifler M et al. Current role of renal biopsy in urologic practice. Urol Clin North Am. 2017 May;44(2):203–11.
[PubMed: 28411912]

Lalani AA et al. Systemic treatment of metastatic clear cell renal cell carcinoma in 2018: current paradigms, use of immunotherapy, and future directions. Eur Urol. 2019 Jan;75(1):100–10.
[PubMed: 30327274]

Motzer RJ et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277–90.
[PubMed: 29562145]

National Cancer Institute. SEER Cancer Statistics Factsheets: Kidney and Renal Pelvis Cancer, 2018. https://seer.cancer.gov/statfacts/html/kidrp.html

Rini BI et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116–27.
[PubMed: 30779529]

Sun M et al. Risk assessment in small renal masses: a review article. Urol Clin North Am. 2017 May;44(2):189–202.
[PubMed: 28411911]

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Renal Cell Carcinoma

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Key Features

Essentials of Diagnosis

General Considerations

Demographics

Clinical Findings

Symptoms and Signs

Differential Diagnosis

Diagnosis

Laboratory Tests

Imaging Studies

Treatment

Medications

Surgery

Therapeutic Procedures

Outcome

Prognosis

When to Refer

References

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