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chemotherapy

Treatment of disease with chemicals or pharmaceutical agents, generally used in reference to treatment of neoplastic disease. Indications: 1) curable by chemotherapy a) acute lymphoblastic leukemia b) acute myeloid leukemia c) Ewing's sarcoma d) gestational trophoblastic carcinoma e) Hodgkin's disease f) non-Hodgkin's lymphoma 1] Burkitt's lymphoma 2] diffuse large cell lymphoma 3] lymphoblastic lymphoma g) rhabdomyosarcoma h) testicular carcinoma i) Wilm's tumor 2) chemotherapy is beneficial a) anal carcinoma b) bladder carcinoma c) breast carcinoma d) chronic lymphocytic leukemia e) chronic myelogenous leukemia f) hairy cell leukemia g) head & neck carcinoma h) small cell carcinoma of the lung i) multiple myeloma j) follicular lymphoma k) ovarian carcinoma 3) chemotherapy may have some benefit a) astrocytoma b) cervical carcinoma c) colorectal carcinoma d) hepatocellular carcinoma e) Kaposi's sarcoma f) non-small cell carcinoma of the lung g) melanoma h) pancreatic carcinoma i) prostate carcinoma j) soft tissue sarcoma 4) ADJUVANT chemotherapy is beneficial a) breast carcinoma b) colorectal carcinoma, stage III c) osteogenic sarcoma d) ovarian carcinoma, stage III e) testicular carcinoma Contraindications: - cancer patients with poor performance status where palliative care may be better option [1] * risk factors for chemotherapy toxicity [16] - >= 1 fall in the past 6 months - limited ability to walk 1 block - social isolation due to physical disability or emotional disorder - hearing loss - needing assistance with medications Adverse effects: 1) see specific agent 2) generally toxicity to rapidly dividing cells: a) bone marrow b) gastrointestinal mucosa c) hair follicles d) toxic erythema [8] 3) myelosuppression: most cytotoxic drugs - major bleeding including intracranial hemorrhage associated with thrombocytopenia [18] - bleeding risk after chemotherapy (10%) [18] - bleeding risk greater for platelet counts < 5000/uL than > 80,000/uL, but no clear pattern of decreasing risk with increasing platelet counts [18] - bleeding risk greater if hematocrit < 25 (RR=1.3), aPTT > 30 (RR=1.4) or > 50 (RR=2.3), INR > 1.2 (RR=1.5) or > 1.5 (RR=2.0) [18] - RBC transfusion or platelet transfusion not associated with diminished next day bleeding [18] 4) nausea/vomiting [13]: - cisplatin doxorubicin, cyclophosphamide - treat with ondansetron or palonosetron + high-dose glucocorticoid [1] 5) gastrointestinal - diarrhea: 5FU, capecetabine, ironotecan - stomatitis, colitis: fluropyrimidines (5-fluorouracil) - colitis, hepatitis: immunotherapy 6) dermatology - alopecia: doxorubicin, cyclophosphamide, paclitaxel - scalp cooling cap may preserve hair in 50% of women - hand-foot syndrome: fluropyrimidines (5-fluorouracil) - pustular acneiform eruptions: EGFR inhibitors 7) mucositis, stomatitis: doxorubicin, methotrexate 8) vesicant: doxorubicin, mitomycin 9) peripheral neuropathy: [21] a) paclitaxel, docetaxel, cisplatin, vincristine b) duloxetine first line for painful peripheral neuropathy [7] 10) pulmonary toxicity (pneumonitis): bleomycin, mitomycin, immunotherapy 12) nephrotoxicity/urogenital: - cisplatin, ifosfamide: renal tubular damage, CKD, cystitis 13) cardiotoxicity: - doxorubicin: dose-related heart failure (irreversible) - trastuzumab: heart failure (not dose-related, reversible) - checkpoint inhibitor: myocarditis, pericarditis 14) endocrine: - immunotherapy: thyroiditis, adrenalitis, hypophysitis 15) gonadal toxicity: - alkylating agents (cyclophosphamide) - carboplatin, doxorubicin 16) musculoskeletal: - osteoporosis: aromatase inhibitors, leuprolide, goserelin 16) carcinogenicity: a) alkylating agents, etoposide, doxorubicin - myelodysplasia, acute myeloid leukemia (AML) b) cyclophosphamide (bladder cancer) c) tamoxifen (endometrial cancer) d) breast cancer chemotherapy: myelodysplastic syndrome, AML 17) extravasation injury: anthracyclines; vinca alkaloids 18) nail changes [20] 19) in older adults (compared with younger patients) [9] - nausea/vomiting & alopecia less prominent - diarrhea & neuropathy are more common - mucositis, cardiotoxicity & central neurotoxicity are more common & more severe in the elderly - myelotoxicity can be more severe & prolonged in the elderly - infections related to myelosuppression may be more common in the elderly [9] Complications: - increased risk for metabolic syndrome, especially with combination chemotherapy [1] - increased risk of cardiovascular disease [1] - cardiovascular risk factors increase cardiotoxicity of chemotherapy [1] - anthracycline cardiotoxicity manifests as irreversible dilated cardiomyopathy - trastuzumab cardiotoxicity presents as reversible LV systolic dysfunction - chemotherapy-induced anemia - treat with packed red cells even if normal iron studies & with nephrotoxic chemotherapeutic agents [24] - cognitive impairment - acknowlege & validate, offer behavioral therapy [1] Mechanism of action: 1) interference with DNA synthesis a) purine/pyrimidine analogues 1] 5-fluorouracil 2] 6-thioguanine b) methotrexate 2) DNA-binding a) alkylating agents 1] cyclophosphamide 2] cisplatin 3] chlorambucil 4] melphalan b) intercalating agents 1] doxorubicin 2] bleomycin 3] mitomycin 4] etoposide (VP-16) 3) microtubule inhibition a) vinca alkaloids 1] vincristine 2] vinblastine b) paclitaxel (Taxol) 4) recruitment of cytotoxic immune-cells (investigational) - bifunctional antibodies that link natural killer-cells with cancer cells [4] * Generally, chemotherapy effective on replicating cells. Mechanism of chemotherapy failure: 1) tumor cell heterogeneity - cells resistant to chemotherapeutic agents a) decreased drug uptake b) increased drug efflux - multidrug resistance due to P-glycoprotein c) decreased drug activation d) increased drug inactivation e) increased production of target enzyme 2) large number of non-cycling or resting cells 3) pharmacologic sanctuaries a) blood-tissue barriers b) blood supply-tumor barriers 4) fatty acid 16:4(n-3) in fish oil associated with resistance to chemotherapy [11] - cisplatin specifically cited [11] 5) no age-associated resistance to chemotherapy [9] Comparative biology: - Mullerian inhibiting substance results in complete arrest of follicle development - ovarian reserve remains stable, & contraception is induced for as long as high blood levels of Mullerian inhibiting substance persist - treatment of female mice high levels of Mullerian inhibiting substance protected primordial ovarian follicle damage from carboplatin, doxorubicin, or cyclophosphamide - cessation Mullerian inhibiting substance treatment resulted in normal activation of the ovarian follicles [17] Notes: - patients's often expect cure from palliative chemotherapy [6] - chemotherapy cost almost 60% more, or $90,144/year in hospital than in a community oncology practice, & patients were more likely to visit the emergency department treatment [19] - avoid fish oil during chemotherapy [11] - at home chemotherapy is popular among cancer patients [22]

Related

antineoplastic agent (chemotherapeutic agent) antineoplastic combination (combination chemotherapy) chemotherapy consolidation multidrug-resistance vaccination with intense chemotherapy

Useful

adjuvant chemotherapy consolidation induction

Specific

adjuvant chemotherapy brain intracavitary chemotherapy chemoradiation (CRT) chemotherapy for breast cancer chemotherapy via bladdder irrigation conversion chemotherapy hyperthermic intraperitoneal chemotherapy neoadjuvant chemotherapy palliative chemotherapy regional chemotherapy

General

pharmacologic therapy

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 17, 18, 19. American College of Physicians, Philadelphia 2015, 2018, 2022.
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 678-680
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 527
  4. Bargou R et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 2008 Aug 15; 321:974. PMID: 18703743
  5. Scholl C et al Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 2009 May 29; 137:821 PMID: 19490892 - Luo J et al A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 2009 May 29; 137:835. PMID: 19490893
  6. Weeks JC et al. Patients' expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012 Oct 25; 367:1616 PMID: 23094723 - Smith TJ and Longo DL. Talking with patients about dying. N Engl J Med 2012 Oct 25; 367:1651 PMID: 23094729
  7. Smith EM et al Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy. A Randomized Clinical Trial. JAMA. 2013;309(13):1359-1367 PMID: 23549581 http://jama.jamanetwork.com/article.aspx?articleid=1674238
  8. Bolognia JL, Cooper DL, Glusac EJ. Toxic erythema of chemotherapy: a useful clinical term. J Am Acad Dermatol. 2008 Sep;59(3):524-9 PMID: 18694683
  9. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  10. Hurria A, Togawa K, Mohile SG et al Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011 Sep 1;29(25):3457-65 PMID: 21810685
  11. Daenen LGM et al Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil. JAMA Oncol. Published online April 02, 2015. PMID: 26181186 http://oncology.jamanetwork.com/article.aspx?articleid=2212208
  12. Yeh ET, Tong AT, Lenihan DJ et al Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004 Jun 29;109(25):3122-31. PMID: 15226229
  13. Navari RM, Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2016; 374:1356-1367. April 7, 2016 PMID: 27050207 http://www.nejm.org/doi/full/10.1056/NEJMra1515442
  14. Maggiore RJ, Dale W, Gross CP et al Polypharmacy and potentially inappropriate medication use in older adults with cancer undergoing chemotherapy: effect on chemotherapy-related toxicity and hospitalization during treatment. J Am Geriatr Soc. 2014 Aug;62(8):1505-12. PMID: 25041361 Free PMC Article
  15. Klepin HD, Pitcher BN, Ballman KV et al Comorbidity, chemotherapy toxicity, and outcomes among older women receiving adjuvant chemotherapy for breast cancer on a clinical trial: CALGB 49907 and CALGB 361004 (alliance). J Oncol Pract. 2014 Sep;10(5):e285-92. PMID: 25074878 Free PMC Article
  16. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  17. Kano M et al. AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. Proc Natl Acad Sci U S A 2017 Feb 28; 114:E1688. PMID: 28137855 Free PMC Article http://www.pnas.org/content/114/9/E1688 - Woodruff TK. A win-win for women's reproductive health: A nonsteroidal contraceptive and fertoprotective neoadjuvant. Proc Natl Acad Sci U S A 2017 Feb 28; 114:2101. PMID: 28213496 http://www.pnas.org/content/114/9/2101
  18. Uhl L, Assmann SF, Hamza TH et al. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood 2017 Sep 7; 130:1247 PMID: 28679741
  19. Nelson R Community Cancer Care 'Much Cheaper' Than Hospital Medscape - Oct 11, 2017. https://www.medscape.com/viewarticle/886890 - The Value of Community Oncology. Site of Care Cost Analysis. Xcenda. Sept 25, 2017 https://www.communityoncology.org/wp-content/uploads/2017/09/Site-of-Care-Cost-Analysis-White-Paper_9.25.17.pdf
  20. Alzahrani MF, AlJasser MI Images in Clinical Medicine: Nail Changes during Chemotherapy. N Engl J Med 2018; 379:1561 PMID: 30332576 Free full text https://www.nejm.org/doi/full/10.1056/NEJMicm1801702
  21. Sutton J, Leapman M Chemo-Induced Peripheral Neuropathy is Underreported - Managing this side effect will take better medications, non-drug strategies, and patient-physician communication. https://www.medpagetoday.com/resource-centers/spotlight-her2-positive-breast-cancer/chemo-induced-peripheral-neuropathy-underreported/2650
  22. Mohile SG, Dale W, Somerfield MR et al. Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology. J Clin Oncol. 2018;36(22):2326-2347 PMID: 29782209 PMCID: PMC6063790 Free PMC article https://ascopubs.org/doi/10.1200/JCO.2018.78.8687
  23. At-Home Cancer Treatment Medscape - Video https://www.medscape.com/resource/oncology-cancer-treatment-at-home
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