Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2015.

Erbitux (cetuximab) [package insert]. Branchburg, NJ: Im Clone Systems, Inc.; 2015.

Campath (alemtuzumab) [package insert]. Cambridge, MA: Genzyme Corporation; 2014.

Taxotere (docetaxel) [package insert]. Bridegewater, NJ: Sanofi-Aventis; 2014.

Doxil (doxorubicin) [package insert]. Horsham. PA:Janssen Products, LP; 2015.

Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist.

2007;12(5):601–609.

Tham EH et al. Evaluation and management of hypersensitivity reactions to chemotherapy agents. Postgrad

.

.

.

.

.

.

.

.

.

.

.

.

149.

.

.

.

.

.

.

.

.

.

.

.

.

.

163.

.

Med J. 2015;91(1073):145–150.

Saif MW, Kim R. Incidence and management of cutaneous toxicities associated with cetuximab. Expert Opin

Drug Saf. 2007;6(2):175–182.

Abraxane (paclitaxel) [package insert]. Bridgewater, NJ: Abraxis Bioscience, LLC; 2015.

Reddick WE et al. Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with

high-dose methotrexate. Am J Neuroradiol. 2005;26(5):1263–1269.

Dufourg MN et al. Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE

93 trial for acute lymphoblastic leukemia in children. Leukemia. 2007;21(2):238–247.

Kwong YL et al. Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities. Ann Hematol.

2009;88(3):193–201.

Smith GA et al. High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with

renal insufficiency. J Clin Oncol. 1997;15(2):833–839.

Rubin EH et al. Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group

B trial in patients with acute myeloid leukemia. J Clin Oncol. 1992;10(6):948–953.

Gallego Perez-Larraya J et al. Neurologic complications of intrathecal liposomal cytarabine administered

prophylactically to patients with non-Hodgkin lymphoma. J Neurooncol. 2011;103(3):603–609.

Newton HB. Neurological complications of chemotherapy to the central nervous system. Handb Clin Neurol.

2012;105:903–916.

Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute

lymphoblastic leukemia. J Pediatr Hematol Oncol. 2010;32(7):554–563.

Magge RS, DeAngelis LM. The double-edged sword: Neurotoxicity of chemotherapy. Blood Rev.

2015;29(2):93–100.

Pirzada NA et al. Fluorouracil-induced neurotoxicity. Ann Pharmacother. 2000;34(1):35–38.

Lyros E et al. Subacute reversible toxic encephalopathy related to treatment with capecitabine: a case report

with literature review and discussion of pathophysiology. Neurotoxicology. 2014;42:8–11.

Truman N, Nethercott D. Posterior reversible encephalopathy syndrome (PRES) after treatment with oxaliplatin

and 5-fluorouracil. Clin Colorectal Cancer. 2013;12(1):70–72.

Chun HG et al. Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep. 1986;70(10):1225–

1228.

Warrell RP Jr, Berman E. Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with

delayed central nervous system toxicity. J Clin Oncol. 1986;4(1):74–79.

Merkel DE et al. Central nervous system toxicity with fludarabine. Cancer Treat Rep. 1986;70(12):1449–1450.

DeAngelo DJ et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute

lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood.

2007;109(12):5136–5142.

Berg SL et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory Tcell malignancies: a report from the Children’s Oncology Group. J Clin Oncol. 2005;23(15):3376–3382.

Ngo D et al. Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of

literature. J Oncol Pharm Pract. 2015;21(4):296–300.

Arranon (nelarabine injection) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

Richards A et al. Evaluation of methylene blue, thiamine, and/or albumin in the prevention of ifosfamide-related

neurotoxicity. J Oncol Pharm Pract. 2011;17(4):372–380.

Szabatura AH et al. An assessment of risk factors associated with ifosfamide-induced encephalopathy in a large

academic cancer center. J Oncol Pharm Pract. 2015;21(3):188–193.

David KA, Picus J. Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol.

2005;28(3):277–280.

Ramchandren S et al. Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia. J Peripher

Nerv Syst. 2009;14(3):184–189.

Kanbayashi Y et al. Statistical identification of predictors for peripheral neuropathy associated with

administration of bortezomib, taxanes, oxaliplatin or vincristine using ordered logistic regression analysis.

Anticancer Drugs. 2010;21(9):877–881.

Kanbayashi Y et al. Statistical identification of predictors for paclitaxel-induced peripheral neuropathy in patients

with breast or gynaecological cancer. Anticancer Res. 2013;33(3):1153–1156.

Park SB et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin.

2013;63(6):419–437.

.

166.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

182.

.

.

.

.

.

.

.

.

.

.

Piccolo J, Kolesar JM. Prevention and treatment of chemotherapy-induced peripheral neuropathy. Am J

Health-Syst Pharm. 2014;71(1):19–25.

Pachman DR et al. Therapeutic strategies for cancer treatment related peripheral neuropathies. Curr Treat

Options Oncol. 2014;15(4):567–580.

Pachman DR et al. Management options for established chemotherapy-induced peripheral neuropathy. Support

Care Cancer. 2014;22(8):2281–2295.

Beijers AJ et al. A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with

oxaliplatin administration. Support Care Cancer. 2014;22(7):1999–2007.

Avan A et al. Platinum-induced neurotoxicity and preventive strategies: past, present, and future. Oncologist.

2015;20(4):411–432.

Grothey A et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant

colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29(4):421–427.

Loprinzi CL et al. Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and

magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol.

2014;32(10):997–1005.

Hochster HS et al. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol.

2007;25(25):4028–4029.

Sandler SG et al. Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology.

1969;19(4):367–374.

Albert DM et al. Ocular complications of vincristine therapy. Arch Ophthalmol. 1967;78(6):709–713.

Holland JF et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res.

1973;33(6):1258–1264.

McCarthy GM, Skillings JR. Jaw and other orofacial pain in patients receiving vincristine for the treatment of

cancer. Oral Surg Oral Med Oral Pathol. 1992;74(3):299–304.

Langer T et al. Understanding platinum-induced ototoxicity. Trends Pharmacol Sci. 2013;34(8):458–469.

Peleva E et al. Incidence of platinum-induced ototoxicity in pediatric patients in Quebec. Pediatr Blood Cancer.

2014;61(11):2012–2017.

Citak EC et al. Vincristine-induced peripheral neuropathy and urinary bladder paralysis in a child with

rhabdomyosarcoma. J Pediatr Hematol Oncol. 2008;30(1):61–62.

Carmichael SM et al. Orthostatic hypotension during vincristine therapy. Arch Intern Med. 1970;126(2):290–

293.

Hahn VS et al. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective

therapies. J Am Heart Assoc. 2014;3(2):e000665.

Simunek T et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative

stress and free cellular iron. Pharmacol Rep. 2009;61(1):154–171.

Menna P et al. An introduction to the metabolic determinants of anthracycline cardiotoxicity. Cardiovasc

Toxicol. 2007;7(2):80–85.

Ferreira AL et al. Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem.

2008;6(4):278–281.

Truong J et al. Chemotherapy-induced cardiotoxicity: detection, prevention, and management. Can J Cardiol.

2014;30(8):869–878.

Conway A et al. The prevention, detection and management of cancer treatment-induced cardiotoxicity: a metareview. BMC Cancer. 2015;15:366.

Von Hoff DD et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med.

1979;91(5):710–717.

Steinberg JS, Wasserman AG. Radionuclide ventriculography for evaluation and prevention of doxorubicin

cardiotoxicity. Clin Ther. 1985;7(6):660–667.

Billingham ME et al. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep.

1978;62(6):865–872.

Bristow MR et al. Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J.

1981;102(4):709–718.

Von Hoff DD et al. Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J

Med. 1977;62(2):200–208.

Tan CT et al. Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (idarubicin) in children

with advanced cancer. Cancer Res. 1987;47(11):2990–2995.

193.

.

.

.

.

198.

199.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Villani F et al. Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin). Eur J Cancer Clin Oncol.

1989;25(1):13–18.

Feig SA et al. Determination of the maximum tolerated dose of idarubicin when used in a combination

chemotherapy program of reinduction of childhood ALL at first marrow relapse and a preliminary assessment

of toxicity compared to that of daunorubicin: a report from the Childrens Cancer Study Group. Med Pediatr

Oncol. 1992;20(2):124–129.

Vulsteke C et al. Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer

patients. Breast Cancer Res Treat. 2015;152(1):67–76.

Synold TW, Doroshow JH. Anthracycline dose intensity: clinical pharmacology and pharmacokinetics of highdose doxorubicin administered as a 96-hour continuous intravenous infusion. J Infus Chemother. 1996;6(2):69–

73.

Weiss AJ et al. Studies on adriamycin using a weekly regimen demonstrating its clinical effectiveness and lack

of cardiac toxicity. Cancer Treat Rep. 1976;60(7):813–822.

Torti FM et al. Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Assessment by

endomyocardial biopsy. Ann Intern Med. 1983;99(6):745–749.

Lum BL et al. Doxorubicin: alteration of dose scheduling as a means of reducing cardiotoxicity. Drug Intell Clin

Pharm. 1985;19(4):259–264.

Valdivieso M et al. Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung

cancer: a prospective, randomized study. J Clin Oncol. 1984;2(3):207–214.

van Dalen EC et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane

Database Syst Rev. 2011(6):CD003917.

O’Brien ME et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal

doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast

cancer. Ann Oncol. 2004;15(3):440–449.

Smith LA et al. Cardiotoxicity of anthracycline agents for the treatment of cancer:systematic review and metaanalysis of randomised controlled trials. BMC Cancer. 2010;10:337.

Sieswerda E et al. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic

cardiotoxicity during and after treatment for childhood cancer. Cochrane Database Syst Rev. 2011;

(9):CD008011.

Silber JH et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to

anthracyclines. J Clin Oncol. 2004;22(5):820–828.

Cardinale D et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic

therapy. J Am Coll Cardiol. 2010;55(3):213–220.

Slamon DJ et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer

that overexpresses HER2. N EnglJ Med. 2001;344(11):783–792.

Viani GA et al. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of

published randomized trials. BMC Cancer. 2007;7:153.

Atallah E et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood.

2007;110(4):1233–1237.

Kerkela R et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12(8):908–916.

Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.

Schmidinger M et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J

Clin Oncol. 2008;26(32):5204–5212.

Perez EA et al. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin

Proc. 2008;83(6):679–686.

Jarkowski A 3rd et al. Heart failure caused by molecularly targeted therapies for cancer. Pharmacotherapy.

2011;31(1):62–75.

Wortman JE et al. Sudden death during doxorubicin administration. Cancer. 1979;44(5):1588–1591.

Rowinsky EK et al. Cardiac disturbances during the administration of taxol. J Clin Oncol. 1991;9(9):1704–1712.

Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

Economopoulou P et al. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res.

2015;7:133–143.

Escudier B et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N EnglJ Med. 2007;356(2):125–134.

Maitland ML et al. Initial assessment, surveillance, and management of blood pressure in patients receiving

vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596–604.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

246.

.

248.

249.

Izzedine H et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol.

2009;20(5):807–815.

Polk A et al. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC

Pharmacol Toxicol. 2014;15:47.

Shirali AC, Perazella MA. Tubulointerstitial injury associated with chemotherapeutic agents. Adv Chronic

Kidney Dis. 2014;21(1):56–63.

Launay-Vacher V et al. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the

European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol.

2008;61(6):903–909.

Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol.

2012;7(10):1713–1721.

Willox JC et al. Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a

randomised trial. Br J Cancer. 1986;54(1):19–23.

Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.

Cancer Treat Rev. 1995;21(1):33–64.

Calvert AH et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin

Oncol. 1989;7(11):1748–1756.

Izzedine H. Anti-VEGF cancer therapy in nephrology practice. Int J Nephrol. 2014;2014:143426.

Rixe O et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II

study. Lancet Oncol. 2007;8(11):975–984.

Zhu X et al. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial

growth factor:systematic review and meta-analysis. Am J Kidney Dis. 2007;49(2):186–193.

Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2015.

Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist.

2006;11(6):694–703.

Fermiano M et al. Glucarpidase for the management of elevated methotrexate levels in patients with impaired

renal function. Am J Health-Syst Pharm. 2014;71(10):793–798.

Lawson M et al. Urological implications of cyclophosphamide and ifosfamide. Scand J Urol Nephrol.

2008;42(4):309–317.

Goren MP et al. Pharmacokinetics of an intravenous-oral versus intravenous-mesna regimen in lung cancer

patients receiving ifosfamide. J Clin Oncol. 1998;16(2):616–621.

Mukhtar S, Woodhouse C. The management of cyclophosphamide-induced haematuria. BJU Int.

2010;105(7):908–912.

Sadowska AM et al. Antineoplastic therapy-induced pulmonary toxicity. Expert Rev Anticancer Ther.

2013;13(8):997–1006.

Vahid B, Marik PE. Pulmonary complications of novel antineoplastic agents for solid tumors. Chest.

2008;133(2):528–538.

Vahid B, Marik PE. Infiltrative lung diseases: complications of novel antineoplastic agents in patients with

hematological malignancies. Can Respir J. 2008;15(4):211–216.

Yang JC et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal

cancer. J Clin Oncol. 2003;21(16):3127–3132.

Durant JR et al. Pulmonary toxicity associated with bischloroethylnitrosourea (BCNU). Ann Intern Med.

1979;90(2):191–194.

Sleijfer S. Bleomycin-induced pneumonitis. Chest. 2001;120(2):617–624.

Haupt HM et al. Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of

leukemia. Am J Med. 1981;70(2):256–261.

Gupta N et al. Gemcitabine-induced pulmonary toxicity: case report and review of the literature. Am J Clin

Oncol. 2002;25(1):96–100.

Stoica GS et al. Corticosteroid responsive fludarabine pulmonary toxicity. Am J Clin Oncol. 2002;25(4):340–341.

Wall MA et al. Lung function in adolescents receiving high-dose methotrexate. Pediatrics. 1979;63(5):741–746.

Abdel-Rahman O, Elhalawani H. Risk of fatal pulmonary events in patients with advanced non-small-cell lung

cancer treated with EGF receptor tyrosine kinase inhibitors: a comparative meta-analysis. Future Oncol.

2015;11(7):1109–1122.

Teuwen LA et al. Management of pulmonary toxicity associated with targeted anticancer therapies. Expert Opin

Drug Metab Toxicol. 2015:1–13.

.

.

.

.

.

.

256.

.

.

.

260.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

Barber NA, Ganti AK. Pulmonary toxicities from targeted therapies: a review. Target Oncol. 2011;6(4):235–

243.

Azambuja E et al. Bleomycin lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther.

2005;18(5):363–366.

Thatishetty AV et al. Chemotherapy-induced hepatotoxicity. Clin Liver Dis. 2013;17(4):671–686, ix–x.

Bahirwani R, Reddy KR. Drug-induced liver injury due to cancer chemotherapeutic agents. Semin Liver Dis.

2014;34(2):162–171.

Pratt CB, Johnson WW. Duration and severity of fatty metamorphosis of the liver following L-asparaginase

therapy. Cancer. 1971;28(2):361–364.

Dix SP et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone

Marrow Transplant. 1996;17(2):225–230.

Ayash LJ et al. Hepatic venoocclusive disease in autologous bone marrow transplantation of solid tumors and

lymphomas. J Clin Oncol. 1990;8(10):1699–1706.

Jeha S et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia.

Blood. 2004;103(3):784–789.

Slavin RE et al. Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic

protocols: a clinical-pathologic study of 33 patients. Cancer. 1978;42(4):1747–1759.

Johnson DH et al. Etoposide-induced hepatic injury: a potential complication of high-dose therapy. Cancer Treat

Rep. 1983;67(11):1023–1024.

Kikuchi S et al. Severe hepatitis and complete molecular response caused by imatinib mesylate: possible

association of its serum concentration with clinical outcomes. Leuk Lymphoma. 2004;45(11):2349–2351.

Einhorn M, Davidsohn I. Hepatotoxicity of mercaptopurine. JAMA. 1964;188:802–806.

Bergner N et al. Role of chemotherapy additional to high-dose methotrexate for primary central nervous system

lymphoma (PCNSL). Cochrane Database Syst Rev. 2012;(11):CD009355.

Weiss RB. Streptozocin: a review of its pharmacology, efficacy, and toxicity. Cancer Treat Rep.

1982;66(3):427–438.

Nordstrom BH et al. Liver function test abnormalities in patients treated with small molecule tyrosine kinase

inhibitors. Presented at: International Society for Pharmacoepidemiology Annual Meeting, Brighton, UK, 19–22

August 2010.

Churpek JE, Larson RA. The evolving challenge of therapy-related myeloid neoplasms. Best Pract Res Clin

Haematol. 2013;26(4):309–317.

Faurschou M et al. Malignancies in Wegener’s granulomatosis: incidence and relation to cyclophosphamide

therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–105.

Guerin S et al. Concomitant chemo-radiotherapy and local dose of radiation as risk factors for second malignant

neoplasms after solid cancer in childhood: a case–controlstudy. Int J Cancer. 2007;120(1):96–102.

Dittrich R et al. Fertility preservation in cancer patients. Minerva Ginecol. 2010;62(1):63–80.

Knight S et al. An approach to fertility preservation in prepubertal and postpubertal females: a critical review of

current literature. Pediatr Blood Cancer. 2015;62(6):935–939.

Levine JM et al. Infertility in reproductive-age female cancer survivors. Cancer. 2015;121(10):1532–1539.

Norian JM et al, eds. Cancer: Principles and Practice of Oncology. 10th ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2014.

Perry MC et al, ed. The Chemotherapy Source Book. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2012.

Ragheb AM, Sabanegh ES, Jr. Male fertility-implications of anticancer treatment and strategies to mitigate

gonadotoxicity. Anticancer Agents Med Chem. 2010;10(1):92–102.

Miller DG. Alkylating agents and human spermatogenesis. JAMA. 1971;217(12):1662–1665.

Cheviakoff S et al. Recovery of spermatogenesis in patients with lymphoma after treatment with chlorambucil. J

Reprod Fertil. 1973;33(1):155–157.

Fairley KF et al. Sterility and testicular atrophy related to cyclophosphamide therapy. Lancet. 1972;1(7750):568–

569.

Buchanan JD et al. Return of spermatogenesis after stopping cyclophosphamide therapy. Lancet.

1975;2(7926):156–157.

Viviani S et al. Gonadal toxicity after combination chemotherapy for Hodgkin’s disease. Comparative results of

MOPP vs ABVD. Eur J Cancer Clin Oncol. 1985;21(5):601–605.

Levine J et al. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol.

.

.

.

2010;28(32):4831–4841.

Taksey J et al. Fertility after chemotherapy for testicular cancer. Arch Androl. 2003;49(5):389–395.

Brydoy M et al. Paternity and testicular function among testicular cancer survivors treated with two to four

cycles of cisplatin-based chemotherapy. Eur Urol. 2010;58(1):134–140.

Loren AW et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical

practice guideline update. J Clin Oncol. 2013;31(19):2500–2510.

p. 1999

Micrometastases are present in most solid tumors at the time of

diagnosis. Neoadjuvant therapy was designed to treat micrometastatic

disease before surgery, in hopes of increasing survival. Although it is not

clear whether neoadjuvant therapy increases survival, residual viable

tumor serves as a marker of response to chemotherapy, and

neoadjuvant therapy may reduce tumor size to allow more surgical

options in the patient.

Case 95-3 (Question 1)

When monitoring therapy in children, one has to remember the agerelated differences in measured parameters and large differences in

size. Blood pressures are lower and heart rates and respirations are

higher in younger children. Intake and output need to be considered in

relationship to the patient’s size.

Case 95-1 (Question 3)

It is important to adjust creatinine clearance measurements or estimates

to adult size (i.e., per 1.73 m

2

) to correctly adjust drug doses for renal

function in children.

Case 95-1 (Question 4)

Infants have larger body surface area–weight ratios than older children.

Further, organ function changes rapidly during the first year of life.

Therefore, chemotherapy dosing guidelines in protocols generally

specify how to calculate doses for smaller children and infants (i.e.,

converting to mg/kg dosing from mg/m

2

, or halving doses).

Case 95-2 (Question 2)

Leucovorin, when used with methotrexate, reduces methotrexate-related

toxicities to rapidly proliferating cells. In treating children with high-dose

methotrexate and leucovorin rescue, serum methotrexate concentrations

are measured so that leucovorin will be discontinued at the correct time.

Renal dysfunction, fluid accumulation in the patient, or drug interactions

can slow methotrexate excretion and require prolonged leucovorin

rescue.

Case 95-3 (Questions 3, 4)

Rhabdomyosarcoma is a soft tissue tumor of skeletal muscle origin, and

it is the most common soft tissue sarcoma of childhood, occurring in 3%

of all children with cancer. The two most common histologic types in

children are embryonal and alveolar. Using the combination of

vincristine, dactinomycin, and cyclophosphamide with local control of

surgery or radiation, it is associated with an approximate 75% failurefree survival for patients with non-metastatic disease.

Case 95-4 (Question 1)

Acute lymphoblastic leukemia (ALL) involves replacement of normal

bone marrow elements because of abnormalities in cellular proliferation.

Signs and symptoms relate to the deficiency in normal bone marrow

elements.

Case 95-5 (Question 1)

Important prognostic variables in ALL are based on clinical and

laboratory findings, including age and white blood cells at diagnosis, sex,

race, immunologic classification, cytogenetics, and early treatment

response/minimal residual disease.

Case 95-5 (Question 1)

The treatment of ALL is divided into phases, including remission

induction therapy, central nervous system (CNS) preventive therapy,

consolidation/intensification phases, and maintenance therapy. All

phases are different, each using multiple agents, schedules, and toxicity.

Case 95-5 (Questions 3, 5, 6,

10–12)

p. 2000

p. 2001

Induction treatment is a combination of systemic and intrathecal

chemotherapy that is administered to induce a complete remission.

Given disease-induced morbidity and treatment-related complications,

this early phase of therapy can be associated with considerable

complications.

Case 95-5 (Questions 2, 3)

Central nervous system preventive therapy is a key component of ALL

treatment. Contemporary treatment/preventive regimens are composed

of intrathecal administration of antimetabolite chemotherapy. Central

nervous system radiation is reserved for specialsituations.

Case 95-5 (Questions 4, 5, 7,

8)

The post-induction phase consists of intensified chemotherapy

treatments that are tailored to the specific type of leukemia and the

patient’s response to prior induction therapy.

Case 95-5 (Question 9),

Case 95-6 (Question 4)

Maintenance therapy is the longest phase of ALL treatment and consists

mainly of oral antimetabolite therapy that is less myelosuppressive than

therapies given during the consolidation/intensification phase. Because

of its prolonged length and low disease-related morbidity, this phase is

associated with the highest rates of noncompliance.

Case 95-5 (Questions 10–12)

Patients with relapsed ALL will often achieve a second remission of

their disease but have a high likelihood of further relapses. Various

approaches including intensified chemotherapy or stem cell

transplantation have been used in the treatment of relapse.

Case 95-6 (Questions 1–3)

Non-Hodgkin lymphoma accounts for 10% of childhood cancers. It has

a cure rate of more than 80%. It often presents as a mass in the

mediastinum or as pleural effusions. Masses may be large; therefore,

adjunctive therapies to prevent tumor lysis syndrome and nephropathy

are necessary.

Case 95-7 (Question 1)

PEDIATRIC MALIGNANCIES

In the United States, cancer is the leading cause of disease-related death for children

between 1 and 14 years of age.

1 However, 5-year survival rates for children

diagnosed with many common cancers have improved to greater than 80% because of

the advent of chemotherapy. Approximately 10,270 new malignancies are expected to

occur in children in the year 2017. Acute leukemias are the most common

malignancies of childhood (Table 95-1), and the solid tumors discussed in this

chapter represent 2.5% to 7.0% of all childhood malignancies.

1 Many common

pediatric solid tumors are uncommon in adults. Likewise, many tumors common in

adults occur infrequently in children. In general, sarcomas and embryonal tumors are

common in children, whereas carcinomas predominate in adults.

Small Round Cell Malignancies

Several pediatric malignancies present similarly to one another as small round cells,

making morphologic diagnosis by traditional light microscopy difficult. The less

typical forms of these diseases, such as peripheral primitive neuroectodermal tumors,

extraosseous Ewing sarcoma, extranodal lymphoma, rhabdomyosarcoma, metastatic

neuroblastoma, and some bone sarcomas, are even more challenging.

2 Therefore,

newer techniques aimed at detecting tumor-specific antigens or chromosomal

aberrations have been developed. This information may prove useful in identifying

prognostic subgroups and tumor types in children and adults with cancer. For

example, identification of the t(11;22) chromosomal translocation in both peripheral

primitive neuroectodermal tumors and Ewing sarcomas has resulted in the

classification of both into the Ewing sarcoma family of tumors.

Genetics

Table 95-1

Relative Incidence of Malignancies in Children 0 to 14 Years of Age

1

Malignancy Relative Incidence (%)

Acute lymphoblastic leukemia 26

Central nervous system 21

Neuroblastoma 7

Non-Hodgkin lymphoma 6

Wilms tumor 5

Acute myeloid leukemia 5

Hodgkin lymphoma 4

Rhabdomyosarcoma 3

Retinoblastoma 3

Osteosarcoma 2.5

Ewing sarcoma 1.5

Other histologic types 20

Similar to adult cancers, the association of many pediatric cancers with chromosomal

aberrations or genetic defects is well confirmed. Examples include the association of

Wilms tumor with congenital malformations, acute leukemias with Down syndrome,

and the association of some pediatric cancers with loss of the p53 or retinoblastoma

tumor suppressor genes.

2–4

Carcinogens

The role of carcinogens in pediatric cancer is probably less prominent than in adults

because of the long latency periods

p. 2001

p. 2002

required. Carcinogens, however, are implicated in the etiology of some childhood

cancers.

5 Postnatal exposure to ionizing radiation is associated with increased risks

for acute leukemias, chronic myelogenous leukemia, and solid tumors such as brain,

thyroid, bone, and other sarcomas. Treatment of pediatric malignancies with

alkylators or topoisomerase II inhibitors such as etoposide or doxorubicin is

associated with an increased risk of acute leukemias. Treatment of childhood acute

lymphoblastic leukemia (ALL), especially in those younger than 5 years of age who

received radiation, results in an increased risk of central nervous system (CNS)

neoplasms, leukemia, lymphoma, and other neoplasms later in life. The only welldocumented prenatal carcinogen is diethylstilbestrol, which is associated with an

increased risk of vaginal or cervical cancer in offspring.

6

Patient Age

Patient age can be a factor in pediatric cancer prognoses and their treatments.

Neuroblastoma is the most common malignancy in infants; however, an infant’s

prognosis is typically better than a child’s, which is attributed to the biology of the

disease in this age group.

7

In contrast, infants with ALL tend to have a worse

prognosis than children. The biology and location of rhabdomyosarcomas are often

different in younger versus older children, with younger children having better

overall survival.

8

Age may also be associated with treatment-related toxicity. Children may have

higher susceptibility to radiation-related toxicity than adults. Normal organ

development may be disrupted; the skeletal system and, in children younger than 4

years of age, the brain are particularly susceptible.

7 Prepubertal girls may have a

decreased risk of fertility problems from chemotherapy and, conversely, children

appear to have a greater risk for anthracycline cardiovascular toxicity than adults.

9,10

Treatment of adolescents and young adults has become an interesting issue in

recent years.

11 Because of various referral practices, several of the malignancies that

are most common in this age group (acute leukemias, lymphomas, sarcomas) are

treated by both adult and pediatric oncologists. Historically, this has divided the

available patient data for this population; thus, minimal new treatment-related

information is published. Outcomes for adolescent and young adult patients have not

improved as much in the last 30 years as for either younger or older patients. This

age group has generally had better results when treated on pediatric protocols; the

reasons are not clear, although suggestions have been made that pediatric protocols

are more aggressive, pediatric oncologists are less likely to reduce doses for

toxicity, biology is at higher risk, and fewer data are available on how to determine

appropriate dosages in adolescents and young adults. This dilemma has led to the

Children’s Oncology Group (COG) (described in the next paragraph) and adult

cooperative groups joining together on investigational protocols to pool data

collected from this population so that more meaningful conclusions might be drawn.

Multi-Institutional Research Groups

With the exception of a few pediatric oncology centers, most treatment centers do not

have sufficient numbers of patients with specific diagnoses to scientifically establish

the efficacy of therapeutic regimens within a reasonable time frame. Thus, most

pediatric centers join the COG, the largest pediatric multi-institutional research

group in the United States, Canada, Australia, and New Zealand. Through this

mechanism, clinical trials often can be finished in 3 to 4 years, allowing for more

rapid progress in the treatment of pediatric cancers. The majority of pediatric

hematology and oncology patients in the United States are either treated on a COG

protocol or treated based on the standard treatment arm of a current protocol. There

are also trials available through smaller consortia that specialize in early phase

clinical trials or pilot studies. Unlike the more common adult cancers, few alternative

chemotherapy regimens are available for pediatric malignancies. With the number of

childhood cancer survivors increasing, research is focusing on reducing the longterm risks and complications of treatment modalities. It is important to determine

which patients are at greatest risk from their cancer and to stratify treatments

according to prognoses. Ideally, the minimal treatment needed to produce cure would

be given when the prognoses are good. On the other extreme, maximal treatment

would be given when the prognoses are poor, and potential benefits outweigh the

treatment-associated risks. Progress is already being made in this direction, and the

future holds promise, especially with rapid gains in our understanding of the biology

of cancers.

Late Effects

Late effects can be described as toxicities or complications that either persist or

occur after therapy is finished. Most of the early data on late effects are from adult

Hodgkin lymphoma patients or from children with cancer. Both groups receive

aggressive therapy and often live for years or decades after treatment. Examples of

late effects include joint or bone problems, heart failure, second malignancies,

strokes, and cognitive dysfunction.

12 A group of pediatric institutions have been

collecting data on thousands of pediatric cancer survivors and a sample of their

siblings, comparing the health problems of the two groups. This study is known as the

Childhood Cancer Survivor Study. In 2006, Oeffinger reported data from the study

showing that more than 60% of the survivors had at least one chronic medical

problem, and 27% had a severe or life-threatening health problem.

12 The overall

relative risk of a health problem compared to siblings was 3.3-fold, with specific

risks as high as 54-fold for joint replacements and 15-fold for heart failure. This type

of knowledge has reemphasized the need for clinicians to limit therapies for low-risk

patients and thus reduce late effects and enhance quality of life for survivors. A

website hosted by St. Jude Children’s Research Hospital contains a listing of all

published studies from the Childhood Cancer Survivor Study

(www.stjude.org/ccss). A CureSearch and Children’s Oncology Group–sponsored

website (www.survivorshipguidelines.org) contains an extensive set of guidelines

for the screening and management of childhood cancer survivors. An important

recommendation relating to care of cancer survivors is to ensure that they have a

record of their treatments that they can keep and provide to their health care

providers for the remainder of their lives.

13 This will enable the health care

providers to use publications and guidelines that might help the survivor’s care.

PEDIATRIC SOLID TUMORS

Neuroblastoma

DESCRIPTION, INCIDENCE, AND EPIDEMIOLOGY

Neuroblastoma is a tumor which develops from immature cells originating from the

sympathetic nervous system.

14