225 Hereditary Cancer Syndromes BRCA SYNDROMES Genetics Pathophysiology Cancer types Clinical features Genetic testing Surveillance Prophylaxis BRCA1 Autosomal dominant with variable penetrance, 17q21 Tumor suppressor, granin protein family with zinc finger motif, packaging and export of peptide hormones Breast (19% by age 40, 50% by age 50, 85% by age 70), ovarian (14 45% lifetime risk), prostate (8 16%), colon (6%) Young age of breast cancer, bilateral breast cancer, ER (70%), lobular Breast (50 85%), ovarian (1 cm) adenomas or adenomas with villous histology and/ or high grade dysplasia Antineoplastic Agents Chemotherapeutic agents Alkylating agents Cyclophosphamide (Cytoxan, IV/PO) Ifosfamide (IV) Melphalan (PO) Chlorambucil (PO) Bulsulfan (PO) Carmustine (BCNU, IV) Lomustine (CCNU, PO) Dacarbazine (DTIC, IV) Temozolomide (PO) Streptozocin (IV) Antimetabolites Methotrexate (IV/PO) Pemetrexed (IV) Raltitrexed (IV) Fluorouracil (IV) Capecitabine (xeloda, PO) Cytosine arabinoside (Ara C, IV) Gemcitabine (IV) Hydroxyurea (PO, IV) Thioguanine (6 TG, IV) Mercaptopurine (6 MG, IV) Fludarabine (IV, PO) Chlorodeoxyadenosine (cladribine, IV) Topoisomerase inhibitors Doxorubicin (hydroxydaunomycin, IV) Doxorubicin (liposomal, IV) Daunorubicin (IV) Idarubicin (PO) Epirubicin (IV) Mitoxantrone (IV) Etoposide (IV/PO) Topotecan (IV) Irinotecan (IV) Platinating agents Cisplatin (IV) Carboplatin (IV) Oxaliplatin (IV) Antimicrotubular agents Vincristine (oncovin, IV) Vinblastine (IV) Vinorelbine (navelbine, IV) Docetaxel (taxotere, IV) Paclitaxel (taxol, IV) Activitya Myelo supp Emetogenic risk Alopecia Other major toxicities b Dose c modification BR, GYN, NHL, BMT +++ ++(+) +++ Hemorrhagic cystitis, muco, sterility Renal, hepatic T, SA, NHL MM, BMT NHL, CLL BMT CNS, NHL CNS, NHL NHL, melanoma, SA CNS, melanoma Carcinoid, islet cell +++ ++ ++ +++ +++ +++ ++ ++ + ++ + +++ + + ++ + ++ + + + Hemorrhagic cystitis, neuro Mucositis, sterility Mucositis, sterility Pulmonary Pulmonary, renal, muco, diarrhea, LFT Pulmonary, renal, muco, diarrhea, LFT Flu like symptoms, LFT, photo Photosensitivity Renal, diarrhea, LFT, hypoglycemia Renal Renal Renal Renal Renal Renal, hepatic Renal, hepatic Renal ALL, chorio, leptomeningeal LU, mesothelioma, BR GI, BR GI, BR GI, BR ALL, NHL, leptomeningeal GI, LU, BR, NPC, bladder AML, CML AML ALL NHL, CLL NHL, hairy cell leukemia + +++ ++ +++ ++ +++ ++ + + Muco, diarrhea, LFT, renal, pulm, neuro Renal, hepatic ++ ++ + ++ +++ + + + + +(+) + + ++ + ++ Mucositis, diarrhea, hand foot Mucositis, diarrhea, LFT, fatigue Muco, diarrhea, hand foot, cerebellar Muco, diarrhea, LFT, hand foot, neuro Mucositis, diarrhea, cerebellar Renal Renal Hepatic Renal Renal, hepatic, neuro Renal, hepatic ++ + ++ Diarrhea, LFT, flu like, rash ++ ++ ++ ++ ++ + + + + + + + + + + Mucositis, rash Mucositis, diarrhea, LFT Mucositis, diarrhea, LFT Neuro, AIHA, LFT Constipation, fever Renal Hepatic Renal, hepatic Renal BR, SA +++ ++ +++ Cardiac Hepatic KS, OV AML, neuroblastoma AML BR AML, BR, prostate LU, T, NHL OV, LU GI, LU, GYN ++ +++ +++ +++ ++ ++ +++ ++ + ++ ++ ++ + + + + +++ +++ +++ +++ + +++ +++ +++ Cardiac, infusion, skin Cardiac Cardiac (less) Cardiac Cardiac, LFT Neuro, LFT Diarrhea, constipation, fever Diarrhea, constipation, fever Hepatic Hepatic Hepatic, renal Hepatic Hepatic Hepatic, renal Renal Hepatic Bladder, LU, T, OV Bladder, LU, T, OV GI ++ ++ + +++ ++ ++ + + + Renal, neuro, ototoxicity Renal, neuro, ototoxicity (less) Neuro, diarrhea Renal, neuro Renal Neuro, renal NHL T, NHL LU, BR BR, LU, prostate, OV ++ ++ ++ + + + + ++ ++ +++ +++ Hepatic, neuro Hepatic, neuro Hepatic Hepatic BR, LU, prostate, OV ++ + +++ Neuro, constipation Cramps, neuro, constipation Neuro, constipation, diarrhea Infusion, neuro, nails, myalgia, arthralgia, edema Neuro, nails, myalgia, arthralgia Hepatic, neuro 227 Antineoplastic Agents Antineoplastic Agents (Cont’d) Chemotherapeutic agents Others Bleomycin (IV) Mitomycin C (IV) Activitya Myelo supp Emetogenic risk Alopecia Other major toxicities b Testicular GI, BR, GU + +++ + + ++ + Pulmonary, hemorrhagic cystitis Pulmonary, HUS, GU irritation Dose c modification Renal Renal a BR breast, chorio choriocarcinoma, BMT bone marrow transplant, CML chronic myelogenous leukemia, CNS brain tumor, GI gastrointestinal, GIST gas trointestinal stromal tumor, GYN gynecological, KS Kaposi sarcoma, LU lung, OV ovarian, MM multiple myeloma, NHL non Hodgkin’s lymphoma, NPC naso pharyngeal carcinoma, SA sarcoma, T testicular, TCL T cell lymphoma b LFT elevated liver enzymes/hepatic dysfunction, muco mucositis, photo photosensitivity c Dose modification may be required for dose-limiting toxicities (in bold) and also potentially renal and hepatic dysfunction Hormonal and targeted agents Activity Cytopenia Other major toxicities Monoclonal antibodies Alemtuzumab (Campath) anti CD52 (SC/IV) Bevacizumab (Avastin) anti VEGF (IV) Cetuximab (Erbitux) anti EGFR (IV) NHL, TCL GI GI, H&N +++ Infusion rx’n, infections (e.g CMV, HSV, TB, fungal), pancytopenia Infusion rx’n, HTN, bleed, thrombosis, GI perforations, proteinuria Infusion rx’n, rash, nail/hair changes, mucositis, diarrhea, hypomagnesemia Infusion rx’n, N&V, diarrhea, fever, LFT Rash, nail/hair changes, mucositis, diarrhea, hypomagnesemia Infusion rx’n, infections (e.g JC virus, CMV, PJP), cardiac arrhythmia Infusion rx’n, cardiomyopathy Gemtuzumab (Mylotarg) anti CD33 (IV) Panitumumab (Vectibix) anti EGFR (IV) Rituximab (Rituxan) anti CD20 (IV) Trastuzumab (Herceptin) anti Her2 (IV) Tyrosine kinase inhibitors Sunitinib (Sutent) VEGFR inhibitor (PO) AML GI NHL BR +++ Renal, GIST + Sorafenib (Nexavar) Renal, liver + CML, GIST + Imatinib (Gleevec) VEGFR inhibitor (PO) bcr/abl, c kit inhibitor (PO) Erlotinib (Tarceva) EGFR inhibitor (PO) Gefitinib (Iressa) EGFR inhibitor (PO) LHRH agonists Goserelin (Zoladex) (IM) Leuprolide (Lupron) (IM) Selective estrogen receptor modulators Tamoxifen (Nolvadex) Aromatase inhibitors Anastrozole (Arimidex) non steroidal (PO) Letrozole (Femara) non steroidal (PO) Exemestane (Aromasin) steroidal (PO) Other hormonal agents Bicalutamide (Casodex) anti androgen (PO) Flutamide (Eulexin) antiandrogen (PO) Finasteride (Proscar) a5 reductase inhibitor Megestrol (Megace) progestin (PO) Fulvestrant (Faslodex) ER blocker (PO) Others Thalidomide (Thalomid) anti angiogenic (PO) Bortezomib (Velcade) proteasome inhibitor (IV) Interferon immune modulatory (IV) Temsirolimus (Torisel) mTOR inhibitor (IV) + Lung Lung Fatigue, diarrhea, acral erythema, nail/hair changes, HTN, bleed, hypothyroidism, hypophosphatemia Fatigue, diarrhea, acral erythema, nail/hair changes, HTN, bleed, hypothyroidism, hypophosphatemia Periorbital edema, nausea, diarrhea, muscle cramps, bowel perforation, fatigue Rash, nail/hair changes, mucositis, diarrhea, interstitial lung dx Rash, nail/hair changes, mucositis, diarrhea, interstitial lung dx Prostate, BR Prostate, BR Hot flashes, mood changes, sexual dysfunction, diarrhea, anemia, loss of muscle mass, osteoporosis BR Hot flashes, mood D, vaginal dryness/discharge, thromboembolism, hypercalcemia, endometrial cancer BR Hot flashes, mood D, arthralgia, vaginal dryness and discharge, osteoporosis for all aromatase inhibitors BR BR Prostate Prostate Prostate BR, endometrial BR Hot flashes, mood changes, sexual dysfunction, diarrhea, anemia, loss of muscle mass, osteoporosis Postural hypotension, sexual dysfunction, dizziness Vaginal bleed and irregularities, nausea, weight gai Hot flashes, nausea, diarrhea, back pain, pharyngitis Myeloma ++ Myeloma, NHL Melanoma, renal Renal ++ ++ + Sedation, fatigue, constipation, rash, peripheral neuropathy, thromboembolism GI symptoms, fatigue, cytopenia, peripheral neuropathy Fatigue, fever, myalgia, LFT, mood changes Rash, mucositis, fatigue, hyperglycemia, hypophosphatemia, hypertriglyceridemia 228 Oncologic Emergencies Oncologic Emergencies INFUSION REACTIONS TREAT UNDERLYING CAUSE stop infusion ABC O2 to keep sat >94%, salbutamol puffs INH q1h PRN, ipratropium puffs INH q6h PRN Diphen hydramine 50 mg IV Â1 dose, hydrocortisone 100 mg IV Â1 dose If hypotensive, give normal saline 500 1000 mL IV bolus and consider epinephrine 0.1 0.25 mg slow IV push (1 mg in 10 mL of NS, give 2.5 mL) May restart chemother apy slowly for most drugs (infusion at 25% rate Â5 min, then 50% rate Â5 min, then 75% rate Â5 min, then complete infusion at 100% rate) PROPHYLAXIS (before treatment) dexamethasone 20 mg PO 12 h and h prior and 10 mg IV 30 prior, diphenhydramine 50 mg IV 30 prior, raniti dine 50 mg IV over 10 and 30 prior, ephedrine 30 mg PO 30 prior See p 372 for more details on anaphylaxis MALIGNANT SPINAL CORD COMPRESSION PATHOPHYSIOLOGY tumor invasion of epidural space (usually above L1 level) ! surrounds thecal sac ! obstruction of epidural venous plexus ! vasogenic edema in white and subsequently gray matter ! spinal cord infarction; 60% T spine, 30% L spine, 10% C spine Median survival post spinal cord compression is months CAUSES prostate cancer, breast cancer, lung can cer, renal cell carcinoma, non Hodgkin’s lymphoma, multiple myeloma, cancer of unknown primary, color ectal cancer, sarcoma CLINICAL FEATURES back pain (particularly may worsen with recumbency), radicular pain (band like in abdomen, legs), weakness (hip flexion, arm exten sion), reflexes (hyperreflexic, Babinski upgoing), sen sory loss (usually levels down from actual lesion, NO sacral paresthesia), Lhermitte’s sign, retention/ incontinence (urinary, bowel), gait ataxia DIAGNOSIS important to have a high index of suspicion as the diagnosis tends to be delayed until patients have incontinence or difficulty walking Clin ical examination followed by spine imaging (X ray, bone scan, CT, MRI) MRI and myelogram are best Strongly consider imaging of T and L spine regard less of clinical findings TREATMENTS corticosteroid (dexamethasone 10 mg IV/PO Â1 dose, then mg IV/PO BID Treat underlying cause urgently (radiation Ỉ radical resection, chemotherapy for chemosensitive tumors) MALIGNANT CAUDA EQUINA SYNDROME PATHOPHYSIOLOGY compression of lumbosacral nerves roots (lower motor neurons, mostly below L1 level) CLINICAL FEATURES lower limb weakness, depressed tendon reflexes in legs and sacral paresthesia DIAGNOSIS similar to malignant spinal cord compression TREATMENTS similar to malignant spinal cord compression SUPERIOR VENA CAVA SYNDROME PATHOPHYSIOLOGY invasion or external com pression of the SVC by contiguous pathologic pro cesses involving the right lung, lymph nodes, and other mediastinal structures, or by thrombosis of blood within the SVC Venous collaterals establish alternative pathways, despite well developed collat eral drainage patterns, central venous pressures remain high, producing characteristic signs and symptoms of SVC syndrome CAUSES neoplasm (NSCLC 50%, SCLC, lym phoma, metastatic cancer, germ cell tumor, thy moma, mesothelioma), inflammatory (fungal infections, TB, sarcoidosis, sclerosing cholangitis), thrombosis (indwelling catheters, pacemaker leads) CLINICAL FEATURES dyspnea, facial swelling and head fullness (especially with bending forward), arm edema, cough, stridor, cyanosis, plethora, venous distension on face, neck, and chest wall DIAGNOSIS CXR, CT chest, bilateral venography For patients presenting with SVC syndrome and sus pected cancer, tissue diagnosis is required (supracla vicular lymph node, sputum cytology, mediastino scopy, thoracentesis, bronchoscopy) TREATMENTS elevate patient’s head Treat underlying cause (radiation, chemotherapy for che mosensitive diseases) Dexamethasone mg PO q6h (for lymphoma and thymoma) Consider endovascu lar stenting if urgent or refractory disease NEJM 2007 356:18 Related Topics Febrile Neutropenia (p 236) Spinal Cord Compression (p 228) 229 Chemotherapy-Induced Nausea and Vomiting HYPERCALCEMIA PATHOPHYSIOLOGY local osteolytic hypercalce mia 20% (cytokines), humoral hypercalcemia of malignancy 80% (PTHrP), 1,25(OH)2vitD secreting lymphomas, and ectopic hyperparathyroidism (PTH) are all known mechanisms Median survival of month post presentation with hypercalcemia CLINICAL FEATURES bony pain, abdominal pain, constipation, polyuria, renal failure, renal stones, confusion DIAGNOSIS Ca, PO4, albumin, PTH, 1,25(OH)2vitD, bone scan SYMPTOM CONTROL NS 200 500 mL/h IV Ỉ fur osemide 20 40 mg IV TID PRN If malignancy and Ca >3.2 mmol/L [>12.8 mg/dL], bisphosphonates (pamidronate 60 90 mg in 500 mL NS IV over h, zoledronate mg in 50 mL NS IV over 15 min), ster oids (prednisone 60 mg PO daily Â10 days, hydro cortisone 200 500 mg IV daily), plicamycin 25 mg/kg in L NS over h, calcitonin 200U SC/IM BID TREAT UNDERLYING CAUSE See HYPERCALCEMIA for more details (p 353) NEJM 2005 352:4 TUMOR LYSIS SYNDROME PATHOPHYSIOLOGY treatment induced lysis of tumor cells, leading to release of cell contents ! TUMOR LYSIS SYNDROME (CONT’D) hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, LDH ! calcium phosphate deposition in renal parenchyma and uric acid nephropathy ! oliguria Usually occurs within days before or days after chemotherapy RISK FACTORS underlying renal insufficiency, hyperuricemia, hypovolemia, increased tumor prolif eration, high chemosensitivity (aggressive lympho mas, ALL, AML, solid tumors) DIAGNOSIS a clinical diagnosis with a combination (but not necessary all) of the following criteria: high uric acid (>475 mmol/L [>4 mg/dL] or 25% from baseline), high K (>6 mmol/L or 25% from baseline), high PO4 (>1.45 mmol/L [>4.5 mg/dL] or 25% from baseline), low Ca (