Oncology .pdf

Oncology Unit March 18 -22, 2024 Day 1 - Introduction to Cancer Epidemiology, Pathophysiology & Risk Factors for Cancer Development Presented to: Physiology II Presented on: Presented by: Ann Marie Flores, PT, MSPT, PhD, Certified Lymphedema Therapist Associate Professor & Director, Cancer Rehabilitation Studies (CARES) Laboratory, PTHMS; Dept. of Medical Social Sciences Director of Cancer Rehabilitation, Cancer Survivorship Institute Robert H. Lurie Comprehensive Cancer Center of Northwestern University [email protected] Cell/text: (615) 364 -2544 Disclosures Financial Disclosures - NCI/NIH 3UM1CA233035-01S1, R01 CA271220 - Lynn Sage Breast Cancer Research Foundation Scholar Award - FDA UG3FD006794 Bias Mitigation - I have used the Feinberg bias checklist to review this lecture to mitigate bias. - I have reviewed this lecture for use of stereotypical or offensive terms, language, etc. - I have, to the best of my abilities, used inclusive language, pronouns, photos and images. - Despite best efforts and intentions, if there is concerning content, please feel free to contact me or report via the bias reporting system. Oncology Unit Overview Day 1 - March 18, 2024: What is cancer? Introduction to cancer epidemiology, pathophysiology, & risk factors for cancer development Day 2 - March 20, 2024: How is cancer treated? Medical management of cancer diagnoses - screening, detection, diagnostic work-up, treatment options Day 3 - March 22, 2024: How does physical therapy help patients with cancer? Principles of oncology physical therapy management r 3/20/23 2 Oncology Unit Objectives Appreciate the prevalence, incidence, mortality & survival from cancer Identify & use terminology to describe cancers and its pathophysiology Identify risk factors that contribute to cancer development Identify signs, symptoms, & tests that clarify a cancer diagnosis Discuss & describe medical treatment for cancer, side effects and adverse events that affect tolerance for medical treatment & implications for rehabilitation – including clinical red flags for emergencies, urgencies, and recurrence Discuss & apply the benefits of cancer rehabilitation, exercise, and physical activity on symptoms, side effects and adverse events of cancer survivors – including the use of clinical practice guidelines 3 Cancer Epidemiology Generally speaking, what is cancer? Accumulation of abnormal cells with unchecked growth potential Mmm Disrespects the environment, interferes w/ normal body functions tobe imonal A dividing breast cancer cell. Credit: National Cancer Institute / Univ. of Pittsburgh Cancer Institute From: https://www.cancer.gov/about-cancer/understanding/what-is-cancer Underlying primary mechanism is still a mystery 10mechs Centers for Disease Control and Prevention, National Center for Health Statistics. O 2nd leading cause of death in the U.S.. National Vital Statistics System, Provisional Mortality on CDC WONDER Online Database. Data are from the final Multiple Cause of Death Files, 2018-2021, and from provisional data for years 2022-2023, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. Accessed at http://wonder.cdc.gov/mcd-icd10-provisional.html on Jan 27, 2024 7:33:12 PM Lopez-Lozaro 2018; Lopez-Lozaro 2016 Basic terms Cancer Survivor: begins with diagnosis and runs through the balance of his or her life. Cancer Prevalence: # people alive today ever diagnosed with cancer. Includes: Call canarpe Newly diagnosed In active curative treatment Completed active treatment Those living with disease Prevalence is derived from long-term incidence & survival rates. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. Cancer Incidence & Prevalence Cancer Incidence: # NEW cases of a specific cancer site (or type) occurring in a specified population during a year, usually expressed as # cancer / 100,000 population at risk Complete Prevalence: Proportion of people alive on a certain day who previously had a diagnosis of the disease, regardless of how long ago the diagnosis was, or if the patient is still under treatment or is "cured". Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. Prevalence - continued Limited Duration Prevalence: Proportion of people alive on a certain day who had a diagnosis of the disease within the past X years (e.g. X= 5, 10, 20 or 25 years). The most common example is 5-year limited duration. FYI - The 5-yr mark coincides with the maximum length of time allowable for NIH R01 grants Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. Survival Observed Survival Rate: uses standard life table procedures & represents the proportion of cancer patients surviving for a specified length of time after diagnosis. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. Cancer Mortality Cancer mortality: # of cancer deaths occurring in a specified population during a year Expressed as # cancer deaths per 100,000 population Cancer Mortality Rate = (Cancer Deaths / Population) × 100,000 Numerator = # cancer deaths Denominator = population size For cancer sites that occur in only one sex, the sex-specific population (e.g., females for cervical cancer) mortality rate is used. Calculated for any given cancer site or for all cancers combined. X Lifetime Risk Lifetime Risk of Developing Cancer Probability of developing or dying of cancer from the time of birth or conditional on a certain age using statistical modeling methods. Where doxwe get the data to calculate cancer statistics? National Program of Cancer Registries Data derived from hospitals (at diagnosis, w/ recurrence, death), death certificates and confirmation from the National Death Index Data aggregated by state Complete data posited in SEER states (more than 80% complete) Access National Program of Cancer Registries at: https://www.cdc.gov/cancer/npcr/ Surveillance, Epidemiology & End Results (SEER) Funded by NCI & CDC Authoritative source for CA statistics Access SEER statistics at http://seer.cancer.gov x Why are these data collected? Policies & funding for health care, research Monitors health of the nation Identifies trends & evaluates effects of public health initiatives Cancer screening Mammography, PSA, fecal occult blood tests, colonoscopy Effects of surgical, chemotherapeutic, radiation, & radiological advances Prevalence of Survivors Over 5% of entire U.S. population By 2040 = 26.0 million an increase of 30% On 6.5 x Chicago population* Nearly 2 x Chicago Metropolitan Area population** * 2020 Chicago population = 2,746,388 ** 2020 Chicagoland (Chicago, Naperville, Elgin, NW Indiana, SE Wisconsin) = 9,618,502 cancer disease of aging 616 601 Occur 65age aging 67% over 65yo 74% over 65yo by 2040 x Estimated Number of Cancer Survivors in the U.S., by Years Since Diagnosis January 1, 2022 lot 5T 20 t Estimated Number of Cancer Survivors in the U.S., by Cancer Type January 1, 2022 sexspecific L t Prevalence of Survivors by Cancer Type 2023 Percentage Other 34% Breast 22% Prostate 20% Gynecological 8% Colorectal 8% Melanoma 8% Breast Prostate Colorectal Melanoma Gynecological Other Estimated Number of Cancer Survivors in the U.S., by Cancer Type - Females January 1, 2022 Estimated Number of Cancer Survivors in the U.S., by Cancer Type - Males January 1, 2022 % of US Population Living w/ Prior Diagnosis of Cancer by Current Age January 1, 2022 MSF survivors Pinndence w Rates of New Cancer Cases by Race/Ethnicity (incidence) 2015 - 2019 white black hispanic Rates of New Cancer Cases (incidence) by Race & Ethnicity for Males & Females 2015 - 2019 DD Cancer Mortality non hispanic black u cancer All sites combined, ageadjusted mortality rates, 2000 – 2020 by race/ethnicity, both sexes, all ages https://seer.cancer.gov/statistics-network/explorer Ninadinee Amortality Estimated Numbers of Individuals Living with Metastatic Cancer in the US Jan 1, 2018 C Covid-19 Potential Impact on Cancer caner screenings oncancer care Outcomes delayed new cancer diagnoses a A cancerrelated deaths Cancer Facts and Figures 2021. 8 How did Covid affect cancer care in the U.S.? Delayed CA screenings, 3/2019 – 5/2020 BCA - 90% Colorectal - 85% Cervical – 94% Decrease in New CA Diagnoses & Rise in CA Related Deaths, 3/2019 – 4/2020 New CA dx reduced by 65% 3.2% increase in CA-related death Delayed CA care 38% reduction in CA surgery Jabbal IS, Sabbagh S, Dominguez B, Itani M, Mohanna M, Samuel T, Nahleh Z. Impact of COVID-19 on Cancer-Related Care in the United States: An Overview. Current Oncology. 2023; 30(1):681-687. https://doi.org/10.3390/curroncol30010053 COVIDSurg Collaborative. Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans. Br J Surg. 2020 Oct;107(11):1440-1449. doi: 10.1002/bjs.11746. Epub 2020 Jun 13. PMID: 32395848; PMCID: PMC7272903. Disparities of Survival Experiences breast cancer Most BCS samples describing side effects are majority white, middle-income, & insured. Caan B et al.Cancer Causes Control. 2005 Jun;16(5):545-56. AAs & economically disadvantaged bear greatest cancer burden gentry canon dying from cancer Return to work ≧ 3 months later IF AT ALL Sig. more later stages diagnosed I then write counter Sig. higher mortality Wagner et al. Cancer. 2012 Aug 15;118(16):4032-45. Tian et al. Womens Health Issues. 2012 MayJun;22;(3):e267-76. Sail et al. Ethn Health. 2012;17(3):309-23. How does all of this spillover into functional rehab outcomes? is Financial Toxicity of Cancer Care 2015: $190.2 billion 2020: $208.9 billion In 2019: Per-patient annualized average costs varies by phase of cancer care continuum (SEER-Medicare data): Initial diagnosis: $45,390 ($43,516 medical services + $1,874 Rx drugs) Continuing: $6,559 ($5,518 + $1,041) Last year of life: $114,099 ($109,727 + $4,372) Mariotto AB, Enewold L, Zhao J, Zeruto CA, Yabroff KR. Medical Care Costs Associated with Cancer Survivorship in the United States. Cancer Epidemiol Biomarkers Prev. 2020 Jul;29(7):1304-1312. doi: 10.1158/1055-9965.EPI-19-1534. Epub 2020 Jun 10. PMID: 32522832; PMCID: PMC9514601. Cancer Deepens Health Inequities Social determinants of health affects time of getting into care Socioeconomic status & insurance status Household income, education, occupational prestige, employment Uninsured/underinsured Race/ethnicity Sex, gender, sexual orientation Employment & marital status Access to care – proximity to health care I More likely to be diagnosed with advanced, later stage cancers More complicated, extensive & costly plans of care Less successful treatment American Cancer Society, Cancer Facts & Figures 2021 Flores AM et al 2016, 2018, 2020 33 32 wage o Amortality rate 10d while Mexicans: 31.5% before 50yo NHW: 8.9% before 50yo CA-related physical & functional impairments are high, under-detected, & rehabilitation is under-utilized despite few barriers. Those w incomes ≤ $10k more likely to report Adj. OR (95%CI) - - % 3 - 4 impairments > 10 years Barriers to PT utilization n = 70 Costs too much 12.9% Single biggest barrier No health insurance ≥6 months 10% PT not recommended 0.8 more average impairments Muscle weakness : 2.21 (1.00 - 4.86) Pain: 2.66 (1.23-5.76) Postural abnormalities: 1.88 (1.67-5.31) than incomes > $40k p=.006 - PT recommended < 18% Funding: NCI/NIH R21CA137483 (PI Flores) & R01CA092447 (PI Blot; Co-I Flores) PT not recommended by Dr. 28.6% Funding: TIER 1 Grant Award, Northeastern University. MPIs Flores & Tucker Cancer Terminology Glossary y carcinoma benign Manne I solid non abnormal solid enitem melanoma pianent mass summa convene otinominicel liquid tumor Be lymphoma Tumor: swelling, growth lesion (same as “mass”) lymphatic Neoplasm: “new growth” = tumor Lesion: damaged tissue due to injury or disease Benign tumor: NOT cancerous Malignant tumor: cancerous 37 Glossary BENIGN TUMORS MALIGNANT TUMORS NOT cancer CANCER Grow slowly Grow rapidly Well-defined capsule contained Not encapsulated Not invasive Invades local structures Well-differentiated Poorly differentiated meant in grain Low mitotic index woman High mitotic index Do not metastasize Can spread distantly (metastasize) Glossary Malignancy: Cancer, carcinoma Solid tumor Abnormal mass of tissue Solid tumors can be either benign or malignant Non-solid tumor AKA liquid tumors Leukemias Abnormal growth of blood cells 13 How cancers are named prefix on gining and How cancers are named... Benign tumor Organ tissue + “-oma” Example: osteoma (benign bone), lipoma (benign fat) Malignant tumor Organ tissue + “- carcinoma” or “- melanoma” or “- sarcoma” Ex: osteosarcoma (bon cancer), breast ductal carcinoma (breast cancer in the milk ducts) Primary vs Secondary tumor nutrition larises arene gone 41 Naming Malignancies Malignancy Term Carcinoma 85-90% did Melanoma ~5% Sarcoma less than 2% Leukemia ~2% Niaid Lymphoma ~5% Features Solid tumor Origin - Epithelial cells Ductal/glandular organs Solid tumor Origin - Pigment-producing cells Commonly skin, can also be internal Solid tumor Origin - Connective tissue Non-solid tumor Origin - bone marrow Non-solid tumor - but can involve spleen, thymus Origin - Lymphatic system Sub-types - Hodgkin’s and Non-Hodgkin’s 42 Glossary Tumor cell characteristics Hyperplasia: increased # cells in a specific area It abnormal Dysplasia: abnormal cell changes, can be seen on microscope, can lead to riskfallor cancer development Neoplasm: abnormal benign or malignant mass; benign may be large but not spread; Malignant can spread; AKA: tumor In situ: early-stage cancer, contained in original tissue d Invasive: into surrounding tissues I other tissues Metastatic: spread to Anaplasia: loss of cellular differentiation seen in malignant neoplasms Cancer Pathophysiology Recall - Normal Cell Cycle - Balances new cell production programmed cell death (apoptosis) G1 – cell prepares to divide S phase – DNA synthesis G2 – cell organizes & condenses DNA M – mitosis & cell division G0 – cell senescence 45 What does this look like? organized A cells crowded abnormal xwell differentiated invadinglocal tissue https://nci-media.cancer.gov/pdq/media/images/761240.jpg What does this look like? Learnoncology.ca 18 How does cancer develop? General Principles 1. Tumor INITIATION – DNA changes initial cancer cells 2. Tumor PROMOTION – Tumor expands, changes, outcompetes neighboring cells for resources 3. Tumor PROGRESSION - Spread of disease 21 10 hallmarks TUMOR INITIATION Relies on theoretical frameworks - Cancer Hallmarks, Somatic Mutation Theory DNA mutation occurs & pass on mutation as they divide & proliferate Risk of mutations ↑ with age Critical # of mutations is still a mystery - 3? 10? More? Tumor initiation as cells divide – and cells that don’t die Changes in cellular metabolism, tumor microenvironment, microbiomes Bottom line: Process, not an event that involves the cell & its environments... Tomasetti & Vogelstein, 2015 22 BOTH DNA DAMAGE and CELLS THAT KEEP DIVIDING create cancer https://www.learnoncology.ca/ 23 23 Example of cancer cell immortality HeLa cervical cancer cells Biopsied 1951, 1st cloned cells Polio vaccine 1st mass produced cells – 20 tons to date Used in CA, AIDs, radiation exposure, gene mapping, cosmetic research Over 11,000 patents 10 Hallmarks of Cancer + 4 Enabling Characteristics Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Date of Download: 3/9/2024 10 Hallmarks of Cancer Pathophysiology + 4 Enabling Characteristics Unlocking Phenotypic Plasticity Sustaining proliferative signaling Evading growth suppressors Nonmutational epigenetic reprogramming Avoiding immune destruction Enabling replicative immortality Tumor promoting inflammation Polymorphic microbiomes Activating invasion and metastasis Inducing or accessing vasculature Senescent cells Genome instability & mutation Resisting cell death Deregulating cellular energetics Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 53 tumorigenesis t Compton of mang progression vianomine dit Hallmark: Unlocking phenotypic plasticityof stemcells i ii iii stem cells Disruption of cellular differentiation includes: (i) dedifferentiation from mature to progenitor states (ii) blocked (terminal) differentiation from progenitor cell states (iii) transdifferentiation into different cell lineages. stayprogenitor BOTTOM LINE - Tumorigenesis & malignant progression is facilitated through pathways that allow various corruption of normal differentiation of progenitor cells into mature cells of different types/ developmental lineages Hanhanen D. Hallmarks of Cancer: New Dimensions.Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Li J, Stanger BZ. How tumor cell dedifferentiation drives immune evasion and resistance to immunotherapy. Cancer Research. 2020 Oct 1:80(19):4037-4041 Hallmark: Sustaining proliferative signaling Growth signals - “gas pedal” Normal Cells proliferate in response to growth factors binding to the cell surface Gentle step on “gas pedal” to turn on cell growth/division when needed But cancer cells are different dont look like anything “Lead foot” else Growth signals speed up production of new cancer cells Aspeedofsignal tofurthergrow 55 Hallmark: Sustaining proliferative signaling DNA damage activates process of proto-oncogene Proto-oncogenes tent for all growth Normal, non-mutant genes that signal cell growth Turns ON - activated to help cell grow/divide Direct synthesis of proteins that cause proliferation oncogene non ma E.g., Epidermal Growth Factor Receptor (EGFR), RAS gene family Oncogenes (mutated proto-oncogenes) Accelerate proliferation – does not turn off Eg., mutant Ras, HER-2 upregulation Gas pedal stuck - Going too fast! accelerate proliferation 29 Hallmark: Sustaining proliferative signaling Proto-oncogene Oncogene x Point mutations - small scale changes in DNA (delete or add) Gene amplification – duplication of a small piece of a chromosome over & over & over again 10s or 100s of mutated gene are present. Chromosomal translocation – piece of one chromosome moves location 30 Hallmark: Evading growth suppressors TUMOR–SUPPRESSOR Genes Normally... Slow cell cycle allowing time for DNA repair Plication Inhibit proliferation STOP cell division - cell arrest i inactivated cannotstop Broken brakes! ex Rb gene, TP53, BRCA But in cancer cells... Mutated tumor-suppressor genes are INACTIVATED Can’t stop replicating 32 hero of cell division p53 protein action in NORMAL cell cycle – Most studied tumor suppressor An arrest growth Cellular stress or induce all death Transformation-related protein 53 (TP53) signals production of tumor antigen p53 (p53) protein for cellular repair, control of metablic pathways, embryo implantation & driving cells into cell senescence p53 acts at G1 & G2 check points To arrest growth &/or induce apoptosis 59 p53 = guardian of the genome induce all death or no way to fix cellI around gene Enabling characteristic Nonmutational epigenetic programming Within the tumor microenvironment Genetic regulation pathways & networks are corrupted and coopted by aberrant cellular activity, metabolism Epigenome - chemical compounds that modify, or mark, genome to tell it what to do, where to do it, and when to do it. Epigenetic marks aren’t part of DNA but are passed on w/ cells division and subsequent generations Epigenomic changes enhance fitness for proliferative expansion of CA cells. Common characteristic of tumors - hypoxia due to insufficient vascularization limiting blood-borne nutrients Alters translational control asking for more tumor Enables malignant phenotype of cancer cells vascular cells Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Hallmark: Avoiding immune destruction Genetic mutations allow CA cell to avoid death by normal immune cells Inherited DNA mutation continue growth & thrive. RECALL – CA cells can signal the immune system to slow down immune reactions or stop killing CA cells immune avoiding destruction Bottom line – CA cells are masters at immune inhibitory processes Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Messerschmidt JL, Prendergast GC, Messerschmidt GL. How Cancers Escape Immune Destruction and Mechanisms of Action for the New Significantly Active Immune Therapies: Helping Nonimmunologists Decipher Recent Advances. Oncologist. 2016 Feb;21(2):233-43. doi: 10.1634/theoncologist.2015-0282. Epub 2016 Feb 1. PMID: 26834161; PMCID: PMC4746082. Hallmark: Enabling replicative immortality Telomeres = protective ends/caps on chromosomes Telomerase = enzyme, maintains stem & germ cell telomeres Normal cells: Cells LOSE part of telomere with every division Eventually not enough telomere length to duplicate, chromosome unravels Cancer cells: ACTIVATE telomerase for immortality/no senescence to repair telomeres Car never breaks down 37 Telomere Shortening how many time cell can divide Role of Telomeres in Apoptosis Telomere Shortening Lack of Telomere Shortening & CA Cells Telomerase Repairs Telomeres DNA will eventually unravel DNA never unravels Huether& McCance6th edfig 10-13 38 Enabling characteristic Tumor promoting inflammation enrobes Inflammatory response w/ cancer development doesn’t stop Cancer-extrinsic inflammation (triggered by autoimmune diseases, bacterial and viral infections, obesity, smoking, asbestos exposure, excessive alcohol consumption) increases cancer risk & accelerates malignant progression. Cancer-intrinsic inflammation (caused by cancer-initiating mutations) contributes to tumor progression via recruitment & activation of inflammatory cells annalen process Extrinsic & intrinsic inflammation causes immunosuppression in the tumor microenvironment Preferred condition for tumor development Inflammatory TME induce CA cell proliferation, prolong cell survival by initially activating oncogenes & inactivating tumor suppressor genes Zhao, H., Wu, L., Yan, G. et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Sig Transduct Target Ther 6, 263 (2021) Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010). Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008). Ritter, B. & Greten, F. R. Modulating inflammation for cancer therapy. J. Exp. Med. 216, 1234–1243 (2019). Diakos, C. I., Charles, K. A., McMillan, D. C. & Clarke, S. J. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 15, e493–e503 (2014). Enabling characteristic Tumor promoting inflammation extrinsic en noon autoimmune intrinsic tumor itself Inflammation recruitment t inflamof tumerthvine area Bioactive molecules to tumor microenvironment Growth factors, proangiogenic factors, enzymes Tumor-associated inflammation INCREASES outside t inside infler tumorigenesis and progression help sustain tumor ble of infra uncontrolled m of tumor Hc of cytokines 70 Enabling Characteristic Polymorphic microbiomes tinny win org microbiome which elects tumor Polymorphic microbiomes intersect w/ enabling characteristics (tumorpromoting inflammation & genomic instability and mutation), Microbiomes (gut, lung, oral, vaginal/cervical, skin) modulate: Tumor phenotypes Hallmark capabilities in some tumor types. Hanhanen D. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Hallmark: Activating invasion & metastasis Metastasis is multi-stage process Spread of cancer cells from original (primary) tumor to another part of the body Spread via blood or lymph system Forms new tumor in other organs or other tissues of the body Metastasis requires: Detachment from extracellular matrix of tumor Migration through venous system/lymphatics Selective adherence in tissues pretend areas Development of new microenvironment Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 41 Hallmark: Activating invasion & metastasis cont. É beginchewy own micro environ Talmadge & Fidler, 2010 42 Hallmark: Inducing or accessing angiogenesis NORMAL tissues new blood vessel growth happens in wound healing & menstrual cycle Cancer Tumor needs its own blood supply to grow more than 1mm Tumors secrete angiogenic factors Stimulate blood vessel “sprouting” E.g., VEGF, PDGF, bFGF Constantly supplying fuel, never runs out Langiogenesis factors Inducing angiogenesis - Wound healing vs Tumor growth McCance 5th ed p enable all ofor Enabling Characteristic Senescent Cells Cellular senescence = irreversible proliferative arrest Wellemerks no longer dividing Involves release of inflammatory factors & other bioactive proteins (chemokines, cytokines, proteases) induced by: contributes to cancercell t avoidcelldeath Nutrient deprivation, DNA damage, damage to organelles & cellular infrastructure Imbalances of cellular signaling networks Cellular senescence is protective (anti-cancer), under normal circumstances In presence of cancer hallmarks Stimulates tumor development & malignant progression Contributes to cancer cell proliferation, avoidance of apoptosis, induces angiogenesis, stimulates tumor invasion & metastasis, suppresses tumor immunity Hanhanen D. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059; Birch J, Gil J. Nat Rev Cancer. 2019;19:439–53. ; Gorgoulis V, Adams PD, Alimonti A, et al. Cell. 2019;179:813–27; He S, Sharpless NE. Cell. 2017;169:1000–11; Kowald A, Passos JF, Kirkwood TBL. Aging Cell. 2020;19:e13270; Lee S, Schmitt CA. Nat Cell Biol. 2019;21:94–101; Wang B, Kohli J, Demaria M. Senescent cells in cancer therapy: friends or foes? Trends Cancer. 2020;6 :838–57 Enabling Characteristic Genome instability & mutation Genomic instability & mutated cancer cells drive tumor progression Cancer cells spread & dominate local tissue environment Normally, genetic repair mechanisms ensures mutations are low p53 - “guardian of the genome” – normally recognizes and mitigates oncogenic stress by: Stopping cell proliferation Induces apoptosis or cell senescence to reign in accumulating DNA damage to prevent malignancy Cancer tumorigenesis results from increased rates of mutation in: DNA repair genes (e.g., BRCA1 & BRCA2) Tumor suppressor genes (e.g., p53) Oncogenes (e.g., Rat Sarcoma [RAS] gene family - KRAS, HRAS, and NRAS) Hanhanen D. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059; Hallmark: Resisting cell death Most cancers have dysregulated processes of cell death via mutations that: Prevent damage detection Apoptotic signaling within the cell Many different types of cell death blocked in cancer cells Apoptosis (AKA programmed cell death) Hanhanen D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059 Montero J, Haq R. Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics. Cancer Discov (2022) 12 (5): 1217–1232. Hallmark: Resisting cell death cont. Apoptosis Normal self-destruct mechanism Occurs when cell is damaged or growth is excessive Cancer cells do not activate apoptosis E.g., BCL-2 - gene that normally inhibits apoptosis BCL-2 gene mutation overexpressed & inhibits apoptosis more than normal (some lymphomas and colon cancer) Uncontrolled growth Security gate – usually stops progress 79 hypoxic metabolism Hallmark: Deregulating cellular metabolism Cancer cells reprogram energy metabolism Shift to glycolysis lactic acidA Metabolic adaptation supports cancer cell survival, relentless cell division, & kills normal cells Shifts to energy production to glycolysis (inefficient energy producer – 2 ATP/glucose molecule) despite presence of O2 that would normally be used for aerobic metabolism (36 ATP) Why glycolysis? It supports... Metabolism of all 4 major macromolecule classes - carbohydrates, lipids, proteins, nucleic acids Biomass synthesis & energy storage needed for uncontrolled proliferation of cancer cells Ideal environment for tumor cells to survive genomic instability, chronic inflammation & immune escape Perfect storm for tumor progression Dong, Y., Tu, R., Liu, H. et al. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Sig Transduct Target Ther 5, 124 (2020). https://doi.org/10.1038/s41392-020-00235-2 80 What are the risk factors for cancer? Risk Factors for Tumor Initiation Cancer develops when cells pass on damaged genetic information as they divide Multiple ways to damage genetic info/DNA: Hereditary causes (~5-10%) Non-hereditary causes (~90-95%) Inflammation Environment/lifestyle Epigenetics 82 Tumor Initiation Hereditary risk DNA mutation passed from parent to child ONLY 5-10 % of cancer is caused by a genetic inheritance When turnedoff E.g., BRCA1/BRCA2 mutations account for ~20- 25% of hereditary breast cancers 83 Tumor Initiation: Non-hereditary risk Inflammation Inflammation alters local cell environment & immune surveillance Chronic inflammation = sustained tissue damage -> lesion formation -> dysplasia/tumor initiation & promotion E.g., Hot tea, smoking, stomach ulcers, cirrhosis Stone et al, 2018; Grivennikov et al, 2010 52 Tumor Initiation: Non-hereditary risk factors Environmental Age Tobacco use Diet Alcohol, Folate Obesity Physical activity Radiation Ionizing, UV, Electromagnetic Rumgay H, Shield K, Charvat H, et al. Global burden of cancer in 2020 attributable to alcohol consumption: A population-based study. The Lancet Oncology. 2021;22(8):1071-1080. doi:10.1016/s1470-2045(21)00279-553 L Tumor Initiation: Non-hereditary risk factors Environmental (cont.) Reproductive/sexual history/traits Infection 13% of all cancer cases in 2018 Viruses – e.g., Hep B/C; Epstein-Barr; HPV Bacteria – H. Pylori Occupational exposure/pollution Cities; farms; downwind/downstream of industrial sites 86 Tumor Initiation: Non-hereditary risk factors Environmental (cont.) a mortality a candy Weight/Diet/Nutrition For adults 20 years old and older, BMI is interpreted using standard weight status categories. These categories are the same for men and women of all body types and ages. https://www.cdc.gov/healthyweight/ass essing/bmi/adult_bmi/index.html 87 Tumor Initiation: Non-hereditary risk factors Epigenetics EPIGENETIC CHANGES - DNA modifications that do not involve changes in the nucleotide sequence Chemical reactions: modify gene expression, do NOT alter the structure of the DNA Epigenetic silencing = turn off gene expression Epigenetic activation = turn on genes that should be silent Epigenetic changes may “prime” cells to be more susceptible to DNA mutation/damage Holliday, 1987; Falahi et al, 2015; Lopez-Lazaro, 2018 56 Paraneoplastic Syndromes Symptom complexes triggered by cancer but not caused by the tumor mass Effects are remote from neoplastic site Hormone secretions or metabolic abnormalities May be an early sign of cancer (10 – 20%) 89 Paraneoplastic Syndromes Cushing Syndrome: from small cell Scleroderma: carcinoid syndrome lung cancer Autoimmune connective tissue Hormonal disorder, high levels of cortisol. upper body obesity, easily bruise Myasthenia gravis: lung cancer, thymoma Autoimmune neuromuscular disorder, muscle weakness disease, stiffening of skin, blood vessels, muscles, & internal organs Nephrotic syndrome: Hodgkin’s lymphoma Group of symptoms: protein in urine, high cholesterol, swelling Vasculitis: leukemia Inflammation in the blood vessels 90 Thank you! J Oncology Unit March 18 -22, 2024 Day 2: Diagnosis, Staging, and Grading Presented to: Physiology II Presented on: March 20, 2024 Presented by: Ann Marie Flores, PT, MSPT, PhD, Certified Lymphedema Therapist Associate Professor & Director, Cancer Rehabilitation Studies (CARES) Laboratory, PTHMS; Dept. of Medical Social Sciences Director of Cancer Rehabilitation, Cancer Survivorship Institute Robert H. Lurie Comprehensive Cancer Center of Northwestern University [email protected] Cell/text: (615) 364 -2544 Disclosures Financial Disclosures - NCI/NIH 3UM1CA233035-01S1, R01 CA271220 - Lynn Sage Breast Cancer Research Foundation Scholar Award - FDA UG3FD006794 Bias Mitigation - I have used the Feinberg bias checklist to review this lecture to mitigate bias. - I have reviewed this lecture for use of stereotypical or offensive terms, language, etc. - I have, to the best of my abilities, used inclusive language, pronouns, photos and images. - Despite best efforts and intentions, if there is concerning content, please feel free to contact me or report via the bias reporting system. Oncology Unit Overview Day 1 - March 18, 2024: What is cancer? Introduction to cancer epidemiology, pathophysiology, & risk factors for cancer development Day 2 - March 20, 2024: How is cancer treated? Medical management of cancer diagnoses - screening, detection, diagnostic work-up, treatment options Day 3 - March 22, 2024: How does physical therapy help patients with cancer? Principles of oncology physical therapy management 3/20/23 2 Oncology Unit Objectives Appreciate the prevalence, incidence, mortality & survival from cancer Identify & use terminology to describe cancers and its pathophysiology Identify risk factors that contribute to cancer development Identify signs, symptoms, & tests that clarify a cancer diagnosis Discuss & describe medical treatment for cancer, side effects and adverse events that affect tolerance for medical treatment & implications for rehabilitation – including clinical red flags for emergencies, urgencies, and recurrence Discuss & apply the benefits of cancer rehabilitation, exercise, and physical activity on symptoms, side effects and adverse events of cancer survivors – including the use of clinical practice guidelines 3 “What I do not remember signing up for was all the late and longterm side effects of cancer treatment, or maybe I did sign for them in a sort of deal with the devil so that I could finish PT school on time and return to my precancer life of running and being with my friends. We sign on the dotted line to rid the cancer from our bodies, but just like the mortgage, student loans, and back taxes, we end up having to pay in the end. Unfortunately, paying off this debt comes with a high interest rate (a multitude of adverse effects) heaped on top of the principal balance.” Cancer Diagnostic Work-Up 6 7 Warning Signs of Cancer “CAUTION(S)” CAUTION(S) Changes in bowel or bladder habits Long-term constipation, diarrhea; change stool size; urinary pain and blood; change in bladder function (urinary frequency) A sore that does not heal in 6 weeks Skin, mouth (white patches/spots in mouth/tongue, infections, smoking, or other tobacco); genitalia Unusual bleeding or discharge Hemoptysis; blood in the stool (very dark or black), abnormal vaginal bleeding; hematuria; bloody nipple discharge Thickening or lump in breast or elsewhere Any thickened skin (may indicate some breast cancers); lump anywhere (e.g., breast, testicle, lymph nodes (glands), soft tissues Indigestion or difficulty swallowing Persistent, long-term Obvious change in wart or mole Any change in color, size, shape, loses sharp border; darkening, yellowing, reddishness, itching, and excessive hair growth Nagging cough or hoarseness Persistent, long-term Supplemental Signs & Symptoms Unexplained weight loss (>= 10 #), fatigue (extreme tiredness; unrelieved from rest), persistent pain (esp. back, abdomen, headache) Cleveland Clinic. Accessed at: https://my.clevelandclinic.org/departments/cancer/patient-education/wellness-prevention/warning-signs; American Cancer Society. Last Revised: November 6, 2020. Available at: https://www.cancer.org/cancer/diagnosis-staging/signs-and2 symptoms-of-cancer.html Cancer Diagnosis Work-Up – Biopsy, Labs, & Imaging Biopsy of suspicious area Needle biopsy Surgical Biopsy Fine needle aspiration (FNA) fluid/cells/tissue w/ thin needle Core - wide needle sample Needle-localized biopsy – Imaging guided wire w/ hook @ end through hollow needle to mark abnormal area; biopsy taken & wire removed) Labs & imaging Blood, sputum, urine, stool, spinal fluid (lumbar puncture) Plain film (X-ray) radiography Colonoscopy, sigmoidoscopy Mammography, ultrasound CT & MRI PET-CT DEXA bone scan Incisional – sample area Excisional – remove entire area (also healthy margin) Ultrasound-guided Stereotactic (CT or MRI guided) 8 Tumor markers Biochemically measured substances produced by tumors Hormones, gene mutations, proteins, enzymes, antigens, antibodies - Indicate the presence of a neoplasm (malignancy or benign) - Can guide diagnosis, prognosis, and treatment - - Sensitivity to various medical (chemotherapy, immunotherapy) options Responsiveness to treatment Determine prognosis Analyzed with blood sample or tumor - 85 common marker tests - on agn ons tx prognosis 9 Tumor Marker CA Type What’s analyzed? How is it used? Alpha-fetoprotein (AFP) Liver cancer, ovarian cancer, germ cell tumors Blood Diagnosis (stage), prognosis, treatment responsiveness BRCA1 & BRCA2 gene mutations Breast, ovarian, pancreatic, prostate Tumor, blood Determine treatment Carcinoembryonic antigen (CEA) Colorectal, breast, lung Pancreatic, stomach, liver, ovarian Blood Treatment effectiveness, detect recurrence Epidermal growth factor receptor (EGFR) mutation Non-small cell lung cancer and colorectal cancer Tumor Determine treatment & prognosis Estrogen receptor (ER)/progesterone receptor (PR) Breast cancer Tumor Determine treatment HER2/neu (ERBB2) gene amplification, mutations, protein overexpression Breast, ovarian, bladder, pancreatic, non-small cell lung, gastroesophageal, and stomach cancers Tumor Determine treatment Tumor Prognosis, determine treatment (which targeted therapy(ies) will work) PIK3CA (Phosphatidyl Inositol-4,5bisphosphate 3-Kinase Catalytic subunit Alpha) gene mutation Breast, colorectal, non-small cell lung, ovarian Programmed death ligand 1 (PDL1) Non-small cell lung, triple negative breast cancer (TNBC), liver, stomach, gastroesophageal, cervical, bladder, head & neck, Hodgkin lymphoma, aggressive lymphoma subtypes Tumor Determine treatment Prostate-Specific Antigen (PSA) Prostate Blood Diagnosis, assess treatment response, recurrence Tumor Staging TNM t invasion th sing Stage - extent of cancer & relies on: - - Tumor size Nodal involvement Presence of Metastasis TNM status status tumor size nodal involvement pucescy of met Staging - Solid Tumors In Situ – pre-invasive no migration - Stage I - Limited to organ of origin & small - Clinical & pathological staging - also posttherapy, recurrence, & autopsy staging - Clinical (cTNM) - based on patient history, physical exam, imaging, biopsy - Pathological (pTNM) – combines clinical staging w/ surgical pathology results; before adjuvant radiation or systemic therapy. Stage II – Larger than Stage I, same anatomic region; local invasion of organ; possible nodal spread Stage III - Larger invasion of organ; regional nodal spread (surrounding primary organ) - Stage IV - Largest; extensive invasion; distant metastasis(es) - radiation aftersurgery hear Amin M. AJCC Cancer Staging Manual, 8th Edition. American College of Surgeons. 2017. ISBN 10: 3319406175 1 T = tumor size & extent of tumor Amin M. AJCC Cancer Staging Manual, 8th Edition. American College of Surgeons. 2017. ISBN 10: 3319406175 - assessed differently based on involved anatomic structures T4 invasion to adjacent organ w/ Example: Gastric (stomach) cancer distant mets O T3 invasion in serosa T2 invasion in muscle T1 invasion in submucosa Tis in situ (mucosal layer) T0 no evidence of tumor TX No info. about T category for primary tumor, or it is unknown, or cannot be assessed Wu HQ, Wang HY, Xie WM, et al. Scanning photoacoustic imaging of submucosal gastric tumor based on a long-focused transducer in phantom and in vitro experiments. Journal of Innovative Optical Health Sciences. 2019; Vol. 12, No. 03, 1950011. https://doi.org/10.1142/S1793545819500111 N = Nodal involvement/spread N0 - no regional nodal spread N1-N3 - degree of nodal spread w/ progressively distal spread Varies by tumor type # of nodes Nodal location Sub-categories & micrometastasis Example: Colorectal Cancer N0 - No nodal involvement N1 - 1-3 regional nodes N2 - 4-6 regional nodes N3 - 7+ regional nodes Nx - unable to be assessed 8 Amin M. AJCC Cancer Staging Manual, 8th Edition. American College of Surgeons. 2017. ISBN 10: 3319406175 1 M = Distant Metastasis MX: Metastasis cannot be measured M0: Cancer has not spread to other parts of the body M1: Cancer has spread to other parts of the body Amin M. AJCC Cancer Staging Manual, 8th Edition. American College of Surgeons. 2017. ISBN 10: 3319406175 1 pagigisme Tumor Grading - How “aggressive” is the cancer? In general, most tumors are graded as: Based on - Microscopic appearance of cells - Rate of growth (undetermined grade) - Degree of differentiation - Mitotic activity/phase of mitosis - Angiogenesis Grade X: Grade cannot be assessed bloody - Irregular borders Grade 1: Well differentiated (low grade); cells look close to normal Grade 2: Moderately differentiated (intermediate grade) Grade 3: Poorly differentiated (high grade) Grade 4: Undifferentiated (high grade); cells most abnormal Amin M. AJCC Cancer Staging Manual, 8th Edition. American College of Surgeons. 2017. ISBN 10: 3319406175 https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-grade 10 https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-grade tgrade Nsurvival General Relationship Between Tumor Grade & Survival 100% Low grade Patient Survival Rate High grade 0% 1 3 2 Years 4 5 11 Additional Tumor Classification Systems Gleason score - Prostate CA - x Two samples of highest grade are added Score can be 2, or up to 10. Score 8-10 = ↑ mortality FAB type - Leukemia FAB (French, American, British) system Classification for Acute myeloid leukemia (AML) 8 subtypes - MO-M7 based on cell type Clark Levels – Malignant Melanoma Levels I - V - Depth of lesion in mm FIGO Staging System – Cervical, - Level I - epidermis only Endometrial/Uterine, Ovarian - Level II – spread into upper layer of dermis Endometrial example: - Level III – spread into lower layer of dermis Stage I (1) - confined to the uterus - Level IV – spread into reticular dermis - Level V – spread into subcutaneous tissue Stage II (2) - spread to the cervix Stage III (3) - spread to vagina, ovaries, and/or lymph nodes Stage IV (4) spread to bladder, rectum, or organs distant from uterus (e.g., lungs, bones) 18 x Paraneoplastic Syndromes Symptom complexes triggered but not caused by tumor mass Effects remote from neoplastic site Hormone secretions or metabolic abnormalities that can be measured Early sign of cancer (10 – 20%) Causes altered immune system Tumor cells make autoantibodies, cytokines, hormones, or peptides affecting multiple organ systems (e.g., neuro, derm, GI, endo, heme, cardio) Happens before or after diagnosis Monitor to diagnose the occult malignancy and improve patient clinical outcomes. Hapa B, Mahendraker N, Ramphul K. Paraneoplastic Syndromes. [Updated 2023 Mar 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507890/# 19 Paraneoplastic Syndromes x – caused by CA treatment Cushing Syndrome - from small cell lung cancer Hormonal disorder, high levels of cortisol. upper body obesity, easily bruise Myasthenia gravis - Lung cancer, thymoma Autoimmune neuromuscular disorder, muscle weakness Scleroderma - Carcinoid syndrome Autoimmune connective tissue disease, stiffening of skin, blood vessels, muscles, & nternal organs Nephrotic syndrome - Hodgkin’s lymphoma Group of symptoms: protein in urine, high cholesterol, swelling Vasculitis - Leukemia Inflammation in the blood vessels 20 Cancer Treatment: Medical Interventions 15 Cancer Prevention & Control Primary – Eliminating or mitigating cancer risk by: - Adopting healthy behaviors & lifestyles Avoiding tobacco & alcohol use Exercising & physical activity Healthy diet Applying sunscreen to protect against UV exposure Secondary - Cancer screening for early detection Prevent disease progression to malignancy. Examples: Breast - self exam, mammography Colorectal – colonoscopy, fecal occult blood test, colonoscopy Prostate - PSA blood test Cervical cancer - Pap smear Tertiary – Reducing/controlling symptoms & morbidity of cancer Gu KJ, Li G. An Overview of Cancer Prevention: Chemoprevention and Immunoprevention. J Cancer Prev. 2020 Sep 30;25(3):127-135. doi: 10.15430/JCP.2020.25.3.127. PMID: 33033707; PMCID: PMC7523034. Managing symptoms Limiting complications Preventing disability 16 Cancer Treatment Strategies Surgery Systemic chemotherapy Endocrine (hormone) therapy Immunotherapy (biologic, targeted) Radiation Stem Cell Transplant Palliative Care 17 Cancer Surgery - Surgical Oncology 24 Surgery Curative excision - surgery Whole lesion Lymph node dissection: removal of an area of lymph nodes Sentinel lymph node biopsy Amputation Palliative surgery - Relieve pressure or blockage - Control bleeding - Reduce infection risk 25 Surgery Prophylactic Cryosurgery Cryotherapy, liquid nitrogen or cold probe Electrosurgery Laser surgery Mohs surgery 1 layer at a time until cells look normal under microscope Typically used for skin cancers Reconstruction 26 Side Effects of Surgery – PT Scope of Practice Amputation Bowel & Bladder Incontinence Chemotherapy induced neuropathy Fatigue Function loss Infection Lymphocele & seroma Lymphedema & axillary web syndrome Muscle weakness, paralysis Non-healing wounds Pain Postural malalignment Scar tissue adhesions Skin ulceration Chemotherapy - Medical Oncology 28 Chemotherapy Most effective during DNA synthesis & mitosis Most organ cells take 19-33 days to complete one full cycle Chemotherapy is given in cycles to “catch” cells in the most effective stage www.chemocare.com 29 Chemotherapy Combinations of drugs often used Used more frequently when more than one mass present or when a mass cannot be removed surgically Different purposes for use at different times: Induction chemotherapy Shrinks tumor, improves symptoms, may or may not result in a cure primp -Neoadjuvant line bysurgery chemotherapy – also type1st of induction chemotherapy - Shrinks tumor prior to surgery or radiation Adjuvant chemotherapy after surgery - Micro-metastases after surgery 24 Side Effects of Chemotherapy Alopecia to tellbody hair lost Arthralgias Cardiomyopathy Cognitive changes Fatigue GI reactions dear enea Hepatotoxicity liver Metabolic alterations - Ca, glucose, K Myelosuppression Neurotoxicity Pulmonary Toxicity pulmonary fibrosis Renal Toxicity Reproductive Dysfunction Skin reactions period 1 wronging Chemotherapyinduced neuropathy 70 1007 neuropathy A 19 851 otherwise AKA chemotherapy induced peripheral neuropathy Was H, Borkowska A, Bagues A, Tu L, Liu JYH, Lu Z, Rudd JA, Nurgali K, Abalo R. Mechanisms of Chemotherapy-Induced Neurotoxicity. Front Pharmacol. 2022 Mar 28;13:750507. Chemotherapy-Induced Neuropathy (CIN) Caused by cancer chemotherapy agents – most notably Platinum-based (oxaliplatin, carboplatin, cisplatin) Taxanes (paclitaxel, docetaxel and cabazitaxel) Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine) Burgess et al. Oncol Ther. 2021; 9:385–450. Neurotoxic adverse event Generally, interferes w/ axonal transport, causes DNA &/or mitochondrial damage, & alters ion channel activity. Burgess et al. Oncol Ther. 2021; 9:385–450; Zajaczkowska R et al. Int J Mol Sci. 2019;20(6):1451 ‘P’ in CIPN = damage to the peripheral nervous system However, central neurotoxicity also occurs – MORE LATER Burgess et al. Oncol Ther. 2021; 9:385–450 Housley SN et al. Exp Neurol. 2020;331:113354; Sioka C, Kyritsis AP..Cancer Chemother Pharmacol.. 2009;63(5):761–7.. Incidence & Prevalence of Chemotherapy-Induced Neuropathy Overall prevalence of CI(P)N: - 19% - 85% Incidence of OX-based CIPN (OIPN) Acute OIPN: 4–98% Platinum-based: 70–100% Gebremedhn et al. BMC Cancer. 2018;18(1):410 Oxaliplatin most detrimental 3-day peak acute OIPN presents w/ Taxanes: 11–87% Vinca alkaloids: up to 20% Cold-induced hypersensitivity (71%), Sensitivity to swallowing cold food/drink (71%) Throat discomfort (63%) Muscle cramps (42%) Acute OIPN can result in: Prolonged infusion times: 22%infection Chemo dose reduction: 15–43% Discontinued chemo: 6–21.4% Pachman DR et al. J Clin Oncol. 2015;33(30):3416–22. Initial severity of acute OIPN predicts chronic OIPN in 84% of patients after 25 months Gebremedhn EG et al. BMC Cancer. 2018;18(1):410; Park SB et al. Oncologist. 2011;16(5):708–16.; Lehky TJ, et al. Muscle Nerve. 2004;29(3):387–92.; Land SR et al. J Clin Oncol. 2007;25(16):2205–11.; de Gramont A,et al. J Clin Oncol. 2000;18(16):2938–47. Pachman DR et al. J Clin Oncol. 2015;33(30):3416–22; Briani C et al. Peripher Nerv Syst. 2014;19(4):299–306. Oxaliplatin-induced neuropathy as most common example... 1 phase Acute No coasting Severity When does it happen & how is acute different than chronic? 2 phase Chronic Coasting – severity increases & persists after OX-based chemo Sereno M et al. Oxaliplatin induced neuropathy in digestive tumors. Review Crit Rev Oncol Hematol. 2014. Jan;89(1):166-78. coasting operating Other chemotherapy induced neurotoxicity pact Chemotherapy-Induced Cognitive Impairment aka Post-chemotherapy Cognitive Impairment (PCCI) “Chemo brain” Memory, problem solving, concentration, dizziness, etc. ~25% who have had chemotherapy Most return to full cognitive function within 1-2 years Ototoxicity pediatric cancers 36% of adult cancer survivors; 40%-60% survivors of pediatric cancers Vestibular or cochlear (tinnitus, ear pain, hearing loss) Vincristine Paralytic Ileus Vin strive Constipation or paralytic ileus. 32% in patients receiving vincristine + concomitant itraconazole (p = 0.04) Chattaraj, A, Syed MP, Low CA, Owonikoko TK. Cisplatin-Induced Ototoxicity: A Concise Review of the Burden, Prevention, and Interception Strategies. JCO Oncology Practice. Vol 19, Number 5. Endocrine Therapy - Hormone Therapy by Medical Oncology 37 Endocrine Therapy Depends on hormone-sensitivity of cancer cells & reduces recurrence risk block production hormone intervene affect hormone on cancer How it works 1. Block production of hormones 2 types that: anastrozle (Arimidex), letrozole (Femara), exemestane (Aromasin) Blocks aromatase enzyme from converting androgens into estrogen Block production of hormones Interfere with effects of hormones on cancer cells Brest cancer Hormone receptor tests prostate cancer - +/-? Treatment options? Are hormones increasing tumor growth? Al Breast cancer: Aromatase inhibitors e.g., Prostate cancer: Androgen Deprivation Therapy (ADT) 2. Interfere with hormone effects on CA cells gvory Decrease receptors or block receptors on Breast cancer - ER+, PR+ tumor cancer cells Prostate cancer – androgen (testosterone) 3. Used in combination w: surgery radiation dependent used for Resection of hormone-producing gland sonar Ovaries, testes on hormone same HRT Targeted therapy, radiation i HRT blocks interfere conlbo Dosage can be over several years joint pain side effect 38 Side effects of endocrine therapy Breast Cancer Common Hot flashes & night sweats Vaginal dryness Early menopause Less Common Blood clots, CVA Cataracts Constipation New primary CAs – endometrial, uterine Osteopenia, osteoporosis Muscle weakness, fatigue Mood swings, depression, loss of libido Pain w/ breathing, shortness of breath, and cough In men: headaches, nausea, vomiting, skin rash, Pain (e.g., bone, back, musculoskeletal pain, joint pain, in extremities, headache) Prostate Cancer Karzai FH, Madan RA, Dahut WL. Metabolic syndrome in prostate cancer: impact on risk and outcomes. Future Oncol. 2016 Aug;12(16):1947-55. doi: 10.2217/fon-2016-0061. Epub 2016 Apr 12. PMID: 27067408; PMCID: PMC5551937. Common A Low libido & erectile dysfunction Hot flashes, gynecomastia Loss of bone density & risk for bone fractures Muscle loss & reduced physical strength Hyperlipidemia & insulin resistance Weight gain/obesity Mood swings & fatigue Liver damage Bone loss Diarrhea Seizures & falls Itching, rash Myocardial infarction, CVA Mimicking metabolic syndrome Less Common Major long term & late effects of endocrine therapy Peripheral neuropathy O Chemotherapy – mostly OX Sensory or sensorimotor balance, coordination, pain all neuropathies Cardiotoxicity congestive HF CHF, MI, HTN, blood clots, thromboembolism, QT prolongation, bradycardia Joint pain/arthralgias Osteopenia - hormone therapy, chemotherapy, surgery Cancer-Related Fatigue Yeh, 2009 44 Therapeutic Radiation - Radiation Oncology 41 Radiation Therapy Destroys hydrogen bonds between DNA strands in cancer cells Standard external beam - 35-37 txs: 5x/week x 5-6 weeks Fractionated doses: to catch all cells at end of G2 Proton beam - More specific - Higher dose possible - Less tissue injury 42 Radiation Therapy Intensity-modulated radiation therapy (IMRT) Sculpts the beam to shape of tumor minimise damage Minimizes damage to normal healthy tissue Internal radiation – AKA brachytherapy Sealed implant Pellets/seeds, ribbons, wires, needles, capsules, balloons, tubes Prostate, breast, head & neck, cervical, ovarian Systemic - Total Body Irradiation (TBI) nonsolidtumors Leukemia/lymphoma - given before stem cell transplant Eradicate cancer cells Immunosuppression - given so donor stem cells can engraft Lungs & heart often blocked to protect from radiation fibrosis From: http://www.seedos.co.uk/prostate_brachytherapy1.htm 43 Side Effects of Therapeutic Radiation Cardiac toxicity so Bowel/bladder changes Diarrhea Fatigue Hair loss Lymphedema Mouth problems so Nausea/vomiting Pulmonary dysfunction Radiation fibrosis Skin reactions - Do Skin color changes Burns Desquamation Swelling Trouble swallowing Ventkatramani et al, 2014; Stubblefield M & Harris. 2011; Gross et al, 2018.. Radiation Therapy Autoimmunity Diabetes Infection TISSUE INJURY Radiation induced tissue fibrosis o Irritant dust Hypertension Trauma Chemicals Activation of monocytes/macrophages/platelets Release of cytokines & growth factors Fibroblasts Recruitment Proliferation Increased synthesis of ECM* Degradation of ECM *ECM = Extracellular Matrix FIBROSIS Adapted from Figure 2: Generalized sequence of events leading from tissue injury to fibrosis.: O'Sullivan B, Levin W. Late radiation-related fibrosis: pathogenesis, manifestations and current management. Seminars in Radiation Oncology 2003 Radiation induced tissue fibrosis ECM Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol. 2015 Nov;141(11):1985-94. doi: 10.1007/s00432-0151974-6. Epub 2015 Apr 25. PMID: 25910988; PMCID: PMC4573901. Skin colourchanges tbroticchanges Radiation induced tissue fibrosis Stubblefield, 2011; Purkayastha et al, 2019; DiFrancesco T et al, 2020 31 Donald Stem Cell Transplant - Medical Oncology he ma top o Thetbone autologous allogeneic matermy marrow mantra ton 48 Stem Cell Transplantation (SCT) AKA hematopoietic cell or bone marrow stem cell transplantation In addition to certain non-malignant conditions, it is used to treat some malignancies Solid tumors Testicular germ cell Non-solid tumors leukemia myeloma lymphoma Multiple myeloma, Hodgkin & non-Hodgkin lymphoma, leukemias (acute myeloid, chronic myeloid, acute lymphocytic, chronic lymphocytic, myelodysplastic syndrome) Autologous & allogenic Khaddour K, Hana C, Mewawalla P. Hematopoietic stem cell transplantation. StatPearls. May 2023. National Library of Medicine. Purpose of SCT bone marrow stem cells y destroyed by demo or malignancy Curative or provide longer period of disease-free survival Used to treat bone marrow or stem cells that are diseased (malignant) or destroyed by chemotherapy &/or radiation Without stem cells, the immune system cannot be supported SCT infuses healthy stem cells that grow & support immune system Stem cells collected from: Bloodstream (peripheral blood) Umbilical cord blood Bone marrow Gulbis AM, Wallis WD. Chapter 10: Preparative Regimens Used in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapies. Manual of Hematopoietic Cell Transplantation and Cellular Therapies. 2024; pp. 125-143. Elsevier. loan pt stem all GAutologous SCT Patient’s own stem cells are removed, diseased cells removed Healthy cells infused into body after conditioning regimen NO risk of graft rejection Lower risk of infection Engraftment happens quicker than allograft Elevated risk of recurrence Some reintroduced stem cells may have disease 51 donor Allogenic SCT DONOR cells Stem cells replaced with healthy stem cells from donor Best donor by: Matching Human leukocyte antigen (HLA) matched donor Possibly a relative ble A regection Anti-rejection meds (cyclosporine or tacrolimus) given to help prevent graft-versus-host disease (GVHD) & transplant rejection 52 Process of SCT For Allograft - Donor matching Human leukocyte antigen (HLA) typing GF forBC prediction marrow collect Growth factor stimulates production ofbone blood cells & release into bloodstream Collect stem cells from bone marrow aspiration (ant. or post. Iliac crest) Mobilization & Collection Gulbis AM, Wallis WD. Chapter 10: Preparative Regimens Used in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapies. Manual of Hematopoietic Cell Transplantation and Cellular Therapies. 2024; pp. 125-143. Elsevier. Timeline of SCT 1. Preparative (conditioning) regimen Inpatient admin chemo w/ or w/o whole body irradiation Destroy cancer cells & suppress immune system to reduce rejection of stem cells Day of hospital admission to Day 0 (transplant day) 2. Transplantation day to engraftment - Infusion fresh or frozen stem cells via IV infusion - low blood counts, side effects, may need blood transfusions - Day 0 to engraftment (blood count recovery) - Engraftment happens b/t Day +10 to +30 - Still immunosuppressed 3. Engraftment Blood counts recover and increase Takes 2 – 6 weeks to forms new white & red blood cells & platelets & immunosuppressed w/ hi risk for infection - 100 days 4. Early convalescence Labs recovering Still immunosuppressed & high risk of infection. High dose steroids. Continual monitoring. Hospital discharge to 1 year after transplant (or longer) 5. Late convalescence immune system almost fully recovered Return to normal activites May develop late complications (e.g., organ dysfunction or recurrence of the original disease). Vaccination - like a child. 1 year after transplant and onward https://www.mskcc.org/cancer-care/patient-education/autologous-stemcell-transplant-guide-patients-caregivers Side Effects of Stem Cell Transplant Infection allo genic Fatigue, Malaise GI & CNS Symptoms Graft vs Host Disease (Allogenic only) ~50% of patients with allogenic stem cell transplant O New immune system sees host body as “foreign” Treated w/ chemotherapy, steroids, targeted therapy Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009 May 02;373(9674):1550-61 Justiz Vaillant AA, Modi P, Mohammadi O. Graft-Versus-Host Disease. StatPearls. NIH. 2022 Graft vs Host Disease (GVHD) RISK after ALLOGENIC SCT Acute (~2 weeks) Skin rash, liver & GI irritations Burning, color alterations, hands & feet Chronic (3-15 months) 5-year survival rate varies b/t 5% – 25% Extensive skin involvement, diarrhea, thrombocytopenia, elevated liver enzymes, Involvement of lung or liver are poor prognostic factors Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009 May 02;373(9674):1550-61 Justiz Vaillant AA, Modi P, Mohammadi O. Graft-Versus-Host Disease. StatPearls. NIH. 2022 Stubblefield MD, Schmitz KH, Ness KK. Physical functioning and rehabilitation for the cancer survivor. Semin Oncol. 2013 Dec;40(6):784-95. 36 Oncologic Emergencies 57 Oncologic Emergencies Type of Emergency A Spinal Cord Compression Superior Vena Cava Syndrome (SVCS) Malignant Pericardial Effusion Signs/symptoms Pain, neurological deficits Initial: Facial/UE redness & edema, SOB Late: Cardio/respiratory/GI symptoms Tumor Lysis Syndrome (TLS) Dyspnea, orthopnea, palpitations, fatigue ↓ absolute neutrophil count (ANC), temp 10 years % - Muscle weakness : 2.21 (1.00 - 4.86) Barriers to PT utilization Single biggest barrier n = 70 - Pain: 2.66 (1.23-5.76) Costs too much 12.9% - Postural abnormalities: 1.88 (1.67-5.31) PT not recommended No health insurance ≥6 months 10% PT not recommended by Dr. 28.6% - 0.8 more average impairments than incomes > $40k p=.006 - PT recommended < 18% Funding: NCI/NIH R21CA137483 (PI Flores) & R01CA092447 (PI Blot; Co-I Flores) Funding: TIER 1 Grant Award, Northeastern University. MPIs Flores & Tucker Primary Outcome - Activity Measure for Post Acute Care Computer Adaptive Test (AM-PACCAT) conducted over telephone Receptivity to receipt of rehabilitation services > 50% not receptive – even among most disabled Rationale for non-receptivity – 5 themes Rehabilitation services would not be beneficial n=84 Rehabilitation is unnecessary n=76 Rehabilitation services are burdensome n=58 Waiting n=38 Too busy for rehabilitation n=31 y Prognosis Term Definition Cure Complete remission for 5 years NED (No Evidence All signs of disease have of Disease) disappeared after treatment Survivor Person Any person from the time of living with/beyond diagnosis until end of life cancer NCI Office of Cancer Survivorship, 2024 Adult survivors of childhood cancers have greater risk of late effects & secondary cancers Cancer Survivorship Care Plans American College of Surgeons Commission on Cancer Standards Tailored for individual patients & includes: Schedule surveillance for recurrence & screen for other cancers Schedule f/u visits, screening tests, & labs Explain common side effects of treatment w/ suggestions for treatment options Screening recommendations for late effects of CA treatment Wellness recommendations aimed to decrease risk of recurrence & improve QOL and overall health Minimum of 3 services offered per year survivorship planning referral rationale ACS CoC Standard 4.6 Rehabilitation Care Services Definition and Requirements Policies and procedures are in place to guide referral to appropriate rehabilitation care services on-site or by referral. “... [R]ehabilitation care services is an essential component of comprehensive cancer care, beginning at the time of diagnosis and being continuously available throughout treatment, surveillance, and, when applicable, through end of life. PT, OT, ST, Physiatry Rehabilitative specialists responsible for screening, diagnosing, and managing physical dysfunction, impairments, disabilities, pain and non-pain symptoms, cognitive function, lymphedema and physical activity recommendations From: https://www.baptistjax.com/doctors Measure of Compliance 1. Policies & procedures to guide referral to appropriate rehabilitation care services on-site or by referral. 2. The process for referring or providing rehabilitation care services to cancer patients is monitored and reviewed by the cancer committee and documented in the cancer committee minutes. National Accreditation Program for Breast Centers (NAPBC) “Survivorship and surveillance begin at the point of diagnosis. The placement of these standards at the end of Chapter 5 should not be construed as an indication that they should only apply post-treatment.” “Examples of evidence-based guidelines include, but are not limited to, the following: Referral to local or online exercise programs Referral to a social worker if psychosocial distress remains elevated post-treatment Referral to outpatient rehabilitation if specific functional complaints arise Referral to outpatient rehabilitation for evaluation and treatment for lymphedema, as needed” “... must use evidence-based guidelines to... address... the following: Appropriate clinical & imaging surveillance for disease progression or recurrence Surveillance for long-term and late effects of disease and treatment For example: Assessing patients for depression, cardiotoxicity, lymphedema, sexual well-being, and sleep disturbance Surveillance for disease, surveillance for long-term and late effects, and requirements for documenting in the patient medical record For example: Patients who receive axillary dissections are automatically referred to rehabilitation for ongoing assessments and, if necessary, lymphedema treatment For services... not available on-site, the NAPBC- accredited program must facilitate access to the necessary resources and services.“ BREAKING NEWS re: PT – March 11 2024 announced March 18 2024 https://cancercontrol.cancer.gov/ocs/special-focusareas/developing-national-cancer-survivorshipstandards?cid=eb_govdel Health System Policy Health System Processes Health System Evaluation/Assessment The organization has a policy that includes... Cancer Survivors are... The organization has a process to collect data on: collection of longitudinal data on survivors experience of survivorship care and patient reported outcomes provided with access and referrals to appropriate supportive health services (e.g., nutrition, occupational & physical therapy, rehabilitation, sexual health, fertility services, dental and podiatry services) caregivers’ experiences and unmet needs Psychosocial Considerations Depression & Anxiety ~ 50% meet criteria for mood, anxiety, adjustment disorders ~4x higher than general population Brunger & Spyra 2016 Anxiety: fear of worsening pain recurrence/spread of cancer, loss of function/independence, change roles, end of life Velthuis et al 2012 Sleep Disturbance: pain, SOB, fear & depression. Sexuality: worry, depression, nausea, pain, fatigue, hormone imbalance Garcia SF et al, 2019; Cheville et al, 2024 Psychosocial Considerations PTSD - avoidance, intrusive recollections Body Image Issues Social Inequality healthdisparities Spirituality Knowledge of/acceptance of diagnosis and prognosis Realistic vs. unrealistic PT goals Partner status Holm, et al 2013 Dasgupta, et al 2016 Physical Therapy for Common Symptoms & Side Effects 11 Common cancer-related impairments Falls under PT scope of practice Cardiovascular Fatigue Deconditioning Tissue fibrosis Cardiovascular tissues – heart, major vessels Genitourinary & Reproductive Urinary & fecal incontinence Dyspareunia & vulvodynia (painful intercourse & vulva) Vaginismus/pelvic muscle spasm Tissue fibrosis Lymphatic & Integumentary Lymphedema Axillary web syndrome Skin integrity & sensation Tissue fibrosis Lymphatics & skin Musculoskeletal Muscle weakness, atrophy, spasm, loss Range of motion & flexibility Abnormal posture Tissue fibrosis Muscle, tendon, ligament Neurological & Neuromuscular Peripheral neuropathy Pain (allodynia,hyperalgesia) Proprioception loss Hyporeflexia Balance, coordination, vertigo Movement disorder & dysfunctional gait Plexopathy & fibrosis Memory loss interfering with physical & functional abilities Aphasia Speech, Swallowing & Hearing Trismus Pain Chronic pain Complex regional pain syndrome Post-mastectomy pain syndrome Pain centralization Phantom Pain Stubblefield M. Cancer Rehabilitation: Principles & Practice, 2nd Edition. New York: Springer Publishing Company. 2019. 30 Physical Activity & Exercise Guidelines Physical Activity & Exercise Physical activity Movement involving skeletal muscle that raises energy expenditure above a resting metabolic rate Exercise Systematic, planned, structured physical activity, w/ specific frequency, intensity, duration & mode to enhance physical fitness Many do not return to pre-diagnosis levels of physical activity & exercise Jones & Alfano 2013; van Haren et al, 2013; Kampshoff et al, 2014; Buffart et al, 2014; Garcia & Thomson, 2014; Mercier et al, 2016; de Boer et al, 2017; Cheville et al, 2017; Toohey et al, 2018 32 Effects of Exercise on Health-Related Outcomes in Those with Cancer What can exercise do? ex parent 7 cancer Prevention of 7 common cancers* Dose: 2018 Physical Activity Guidelines for Americans: 150-300 min/week moderate or 75-150 min/week vigorous aerobic exercise Survival of 3 common cancers** Dose: Exact dose of physical activity needed to reduce cancer-specific or all-cause mortality is not yet known; Overall more activity appears to lead to better risk reduction *bladder, breast, colon, endometrial, esophageal, kidney and stomach cancers **breast, colon and prostate cancers Wh enhance survival for breastcolon t prostate Overall, avoid inactivity, and to improve general health, aim to achieve the current physical activity guidelines for health (150 min/week aerobic exercise and 2x/week strength training). avoid inactinte Outcome Aerobic Only Resistance Only Combination (Aerobic + Resistance) Strong Evidence Dose Dose Dose 3x/week for 30 min per session of moderate intensity 2x/week of 2 sets of 12-15 reps for major muscle groups at moderate intensity 3x/week for 30 min per session of moderate aerobic exercise, plus 2x/week of resistance training 2 sets of 12-15 reps for major muscle groups at moderate intensity 2-3x/week for 30-60 min per session of moderate to vigorous 2x/week of 2 sets of 8-15 reps for major muscle groups at a moderate to vigorous intensity 2-3x/week for 20-30 min per session of moderate aerobic exercise plus 2x/week of resistance training 2 sets of 8 -15 reps for major muscle groups at moderate to vigorous intensity Physical Function 3x/week for 30-60 min per session of moderate to vigorous 2-3x/week of 2 sets of 8-12 reps for major muscle groups at moderate to vigorous intensity 3x/week for 20-40 min per session of moderate to vigorous aerobic exercise, plus 2-3x/week of resistance training 2 sets of 8 -12 reps for major muscle group at moderate to vigorous intensity Anxiety 3x/week for 30-60 min per session of moderate to vigorous Insufficient evidence 2-3x/week for 20-40 min of moderate to vigorous aerobic exercise plus 2x/week of resistance training of 2 sets, 8 -12 reps for major muscle groups at moderate to vigorous intensity Depression 3x/week for 30-60 min per session of moderate to vigorous Insufficient evidence 2-3x/week for 20-40 min of moderate to vigorous aerobic exercise plus 2x/week of resistance training of 2 sets, 8 -12 reps for major muscle groups at moderate to vigorous intensity Insufficient evidence 2-3x/week of progressive, supervised, program for major muscle groups does not exacerbate lymphedema Insufficient evidence Insufficient evidence 2-3x/week of moderate to vigorous resistance training plus high impact training (sufficient to generate ground reaction force of 3-4 time body weight) for at least 12 months Insufficient evidence 3-4x/week for 30-40 min per session of moderate intensity Insufficient evidence Insufficient evidence ahemtoguidelines ofhealthe 150mnaerobic 2xstrongest Cancer-related fatigue Health-related quality of life Lymphedema strenghttraining t prevent exacerbation Moderate Evidence Bone health Sleep Citation: bit.ly/cancer_exercise_guidelines 3/17/24 Moderate intensity (40%-59% heart rate reserve or VO2 R) to vigorous intensity (60%-89% heart rate reserve or VO2 R) is recommended. 33 tx cancer duringtreatment Exercise during cancer Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline aerobic during Clinical Question Recommendation Does exercise during cancer treatment safely improve outcomes related to quality of life, treatment toxicity, or cancer control? Does consuming a particular dietary pattern or food(s) during cancer treatment safely improve outcomes related to quality of life, treatment toxicity, or cancer control? Do interventions to promote intentional weight loss or avoidance of weight gain during cancer treatment safely improve outcomes related to quality of life, treatment toxicity, or cancer control? Type Evidence Quality Strength 1.1. Oncology providers should recommend aerobic and resistance exercise during active treatment with curative intent to mitigate side effects of cancer EB M-L S treatment. Note: Exercise interventions during active treatment reduce fatigue; preserve cardiorespiratory fitness, physical functioning, and strength; and in some populations, improve quality of life and reduce anxiety and depression. In addition, exercise interventions during treatment have low risk of adverse events. Evidence was not sufficient to recommend for or against exercise during treatment to improve cancer control outcomes (recurrence or survival) or treatment completion rates. 1.2. Oncology providers may recommend preoperative exercise for patients undergoing surgery for lung cancer to reduce length of hospital stay and postEB L W operative complications. 2.1. There is currently insufficient evidence to recommend for or against dietary interventions such as ketogenic or low carbohydrate diets, low fat diets, N/A Ins N/A functional foods, or fasting to improve outcomes related to quality of life, treatment toxicity, or cancer control. 2.2. Neutropenic diets (specifically diets that exclude raw fruits and vegetables) are not recommended to prevent infection in cancer patients during active EB L W treatment. 3. There is currently insufficient evidence to recommend for or against intentional weight loss or prevention of weight gain interventions during active treatment to N/A Ins N/A improve outcomes related to quality of life, treatment toxicity, or cancer control. Note: The Expert Panel felt strongly that the current lack of evidence regarding diet and weight management interventions during cancer treatment should be a call to conduct more research in these critical areas. Diet and weight management strategies that provide health benefits to the general population could also provide important benefits to people who are undergoing cancer treatment. The Expert Panel is not discouraging clinicians from discussing healthy diet and weight1,2 with their patients, but did refrain from making specific recommendations, given gaps in the evidence. Abbreviations. EB, evidence based; Ins, insufficient; L, low; M-L, moderate to low; N/A, not applicable; S, strong; W, weak Presentation or Section Title 34 www.asco.org/supportive-care-guidelines ©American Society of Clinical Oncology 2022. All rights reserved. For licensing opportunities, contact [email protected] 3/17/24 when hold exercise t conditions Complete Blood Counts (CBC) – lab values so CAUTION No Exercise Hematocrit (% vol. RBCs) < 25% Hemoglobin (RBCs) < 7g/dL WBC Light Exercise Moderate Exercise 25-30% Ntheno 8-10 g/dl No3platelets < 3000/mm < 500 isolation Above 30% Above 10 g/dL 3-5000/ mm3 Above 5000/mm3 Normal Values F= female M= male F:36 - 48% M:41 - 51% F: 12 - 15.5 g/dL M: 13.5 - 17.5 g/dL 4,500-11,000/mm3 precautions Platelets < 10,000/mm3 < 6000/mm3 10k-20k/mm3 20k-50k/mm3 150k – 400k/mm3 Zheng JY, Mixon AC, McLarney MD. Safety, Precautions, and Modalities in Cancer Rehabilitation: an Updated Review. Curr Phys Med Rehabil Rep. 2021;9(3):142-153; Maltser 2017. immunosurprised Oz delivery 35 Electrolytes Potassium Normal Values Precautions 3.5 - 5.0 mmol/L >5.5 mmol/L (Hyperkalemia) – risk of cardiac arrhythmias, tumor lysis syndrome cardiac changes Calcium cardiacchange E 8.5-10.6 mg/dL pain D Sodium ADH 135–145 mmol/L 10.4mg/dL (Hypercalcemia- neg. prognostic factor mult. Myeloma; widespread bony mets; kidney stones, bone & abdominal pain, mood disorders, & weakness. 200mmHg Resting diastolic pressure > 110 mmHg Orthostatic hypotension Resting heart rate > 140 bpm Respiratory rate < 10 or > 30 breaths/min Temp ≥ 103° Uncontrolled arrhythmias or tachycardia Uncontrolled diabetes Recent embolism Within 2 hours of cancer treatment Yougotrisk O Campbell K, Winters-Stone K, Wiskemann J, et al. Med Sci Sports Exercise. 2019 37 Health-Related Quality of Life Exercise decreases: Mood swings Sleep problems Poor body image Exercise improves healthAnxiety related quality of life: Depression Emotional well being Fatigue Social well-being Physical & functional well being Spiritual well being Brown et al, 2018; Angenete et al, 2016; Lipsett et al 2017; Padilha et al 2017; Buffart et al 2017; Buffart et al. 2013; Mishra et al. 2012 38 Quality of Life Outcome Measures Reported Outcome Measurement Information System (PROMIS) O Patient PROMIS-Pain, Pain Interference, Depression, Anxiety, Physical Function, FACT-G, FACT-B, FACT-HNC, FACT-Lung, etc https://www.healthmeasures.net European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 https://qol.eortc.org/questionnaires/ SF-36 Others... 39 Immune System Response to exercise Cardiorespiratory fitness might be a robust predictor of prognosis after CA diagnosis Lakoski et al, 2012 Sig. improvement in CA-related immune system components due to exercise Fairey et al, 2002 Regular mod. exercise enhances immune function Repeated bouts of vigorous exercise may lead to immunosuppression & reverse effects of CA-treatment Walsh et al, 2012 40 Cancer Risk/Recurrence ACS guidelines - x 5 or more days/week Adults: 30 min (45-60 preferable) moderate to vigorous physical activity, above usual activities Children/adolescents: at least 60 min moderate to vigorous physical activity Physically active women have ↓ risk of breast cancer Strong evidence for colorectal, prostate, breast and endometrial cancer Emerging evidence that physical activity ↓ risk of lung and pancreatic cancer Cormie et al, 2017; Friedenreich et al, 2010; Walsh et al, 2011 41 Cancer-Related Fatigue Cancer-Related Fatigue “Persistent sense of tiredness that interferes with function, is distressing, and requires monitoring and… treatment” NOT proportional to recent activity c More severe, more distressing, less likely to relieve with rest The most reported cancer treatment symptom: 60-100% of people with cancer during treatment, months after, or years after Elevated inflammatory cytokines, elevated cortisol, and cellular dysregulation as associated (but not causal) Outcome Measures: PROMIS-Fatigue, Brief Fatigue Inventory (BFI) & Cancer Fatigue Scale (CFS) Berger et al 2017 ;Bower, 2014; Scott & Posmontier, 2017; Prue et al. 2006; Gerber 2017; Mustian et al. 2017. 18 43 Causes of Cancer-Related Fatigue Primary factors: pain, insomnia, nutrition limitations Chemo factors: hypothyroidism, anemia, ↑cytokines/inflammation Co-morbidities: cardiac, pulmonary, renal, hepatic, neurologic, endocrine (DM), infection, depression System changes that ↓ the supply of O2 to cells Psychosocial & demographic variables Gerber, 2017; Prue et al. 2006; Bower, 2014; Cheville et al 2017 44 CRF & Deconditioning Cycle Cancer treatment often results in ↓ activity level ↓ muscle mass ↓ cardiac output ↓ respiratory capacity Daily activities normally supported by aerobic energy are more supported by anaerobic glycolysis → ↓ in available ATP, ↑ in lactic acid ppain ↑ effort & energy required ↓ activity & ↑ fatigue ↓ activity 45 Clinical Practice Guideline Cancer-Related Fatigue Grade A tools Screening EORTC-QLQ-C30 Assessment PROMIS Fatigue–Short Forms FACIT–Fatigue Piper Fatigue Scale– Revised 46 Exercise for Cancer-Related Fatigue Exercise significant treatment for CRF Alongside resolving any comorbid medical or psychological diagnosis E.g., hypothyroid, immune disorders, depression, seasonal affective disorder, etc... May need cognitive behavioral therapy – also sig. effective. May be more effective than medication Greater treatment effect during active treatment versus after Exercise limits negative physiological changes in muscle mass, cardiac chemotherapy output & respiratory capacity Exercise ↓ effort to do everyday tasks ↓ fatigue ↑ activity every conservation 47 Energy conservation Prioritize activities Pace with rest Use proper body mechanics Be organized Arrange environment tox limit carrying, bending, lifting, distance 3/17/24 48 Cancer-Related Pain Cancer-Related Pain 8 uncontrolledpain N survival 40% survivors living w/ pain 5 – 10% w/ severe, chronic pain that limits function 21% childhood cancer survivors w/ pain Heathcote LC, Eclleston C. Pain 2017; 158:1187-1191 Sex, gender, culture, age, sleep, anxiety, depression affect presentation of pain Survival linked to pain control Temel, et al. 2010 50 Chronic Pain Syndromes Associated with Cancer Treatment - Chemotherapy r contribute to pains osteopenia to stonerosis Paice JA, et al. J Clin Oncol. 2016: 34:3325-3345 51 Cancer-Related Lymphedema Cancer-related lymphedema I cause is of lyMp cancer ttx Risk factors O Damage to lymphatic structures - lymph nodes & vasculature Surgery, radiation, taxane chemotherapy Hx of lymphedema, obesity 8 Abnormal accumulation of proteinrich fluid in the interstitium Persistence of lymphostasis triggers chronic inflammation & tissue fibrosis Progressive resistance exercise is safe & may prevent exacerbation Davies C, Levenhagen K, Ryans K, et al. Phys Ther. 2020 Jul 19;100(7):1163-1179. Schmitz K, et al. NEJM. 2010 Fu et al, 2014 3/17/24 53 https://klosetraining.com/aboutus/about-lymphedema-2/ Burden of Cancer-Related Lymphedema Cancer Site # Articles Pooled N Incidence Range Head & Neck 2 347 breast Gynecological / Genitourinary gynot urine 25 222,472 8080% - 90% 901 14 15,850 Preventive Lymphatic Surgery 7 13,342 Melanoma 3 989 TOTAL 51 253,000 headBreast neck melanoma o Letellier ME, et al. Incidence of Lymphedema Related to Various Cancers and their Treatments. In review. 0% - 74% 411 0% - 41% 5% - 29% 1 1% - 27% 271 0% - 90% Lymphedema Signs & Symptoms Asymmetric edema Slow onset, progressive Pitting, (+) Stemmer’s sign Loss of natural contours Skin changes breakdown Tissue fibrosis RBC Hyperkeratosis Warty outgrowths (papillomas) Skin breakdown, ulcerations Recurrent cellulitis infection bic aprotein Discomfort common Heaviness, achiness, sometimes painful https://www.lymphedemablog.com/2018/01 /03/questions-and-answers-on-head-andneck-lymphedema-hnl/ https://www.researchgate.net /figure/lymphedema-on-theoperated-chest-wall-in-threepatients-front-view-3-monthsafter-the_fig2_304814791 55 WEST AA MSS but h tx Prevalence of Lymphedema Signs & Symptoms By Household Income Agreement Between Lymphedema Signs/Symptoms & Diagnosis of Lymphedema By Race 58 Lymphedema Treatment Complete Decongestive Therapy – Gold Standard Manual lymphatic drainage Compression bandaging Therapeutic exercise Self-MLD, bandaging Meticulous skin & nail care Weight management Compression garment(s) onceplateau owns w lymphedema 59 Lymphedema Clinical Practice Guideline Diagnosis of secondary upper quadrant lymphedema Incorporates prehabilitation approach w/ post-operative monitoring Perdomo M, Ryans K, Levenhagen K, et al. Clinical Implementation of the Clinical Practice Guidelines for Diagnosing Upper-Quadrant Lymphedema Secondary to Cancer Rehabilitation Oncology. 2018 36(3):E11-E18. doi: 10.1097/01.REO.00000000000001 15 60 Interventions for BCRL Early (ISL Stage I): compression garment, HEP, self-management education, if persistent - may need CDT Prehab – Evaluation, HEP, issuance of compression Monitoring for BCRL Moderate/Late Stage (ISL Stages II – III): CDT, may omit MLD, compression, kinesiotape, IPC, monitor volume change over time, LLL Exercise at Risk or ISL Stage 0 All Stages: add myofascial therapy + stretching, exercise, scar massage garment for high risk; MLD may not reduce risk Post-op, every 3 months x 1 yr; biannually x 5 yrs Early stage (ISL Stage 0) – education, selfmassage, compression garment; may need CDT HEP w/ PRE at post-op month 1 Davies C, Levenhagen K, Ryans K, et al. Phys Ther. 2020 Jul 19;100(7):1163-1179. 61 Pathologic Fracture Pathological Fractures Skeletal-related event OSTEOBLASTS lay down new bone OSTEOCLASTS break down old bone to make room for new tissue LYTIC bony lesions – osteoclast activity high BLASTIC lesions – osteoblast activity high 80% of bone metastasis are from Breast, Lung, Thyroid, Multiple myeloma, Kidney, Prostate “BLT with Mayo and a Kosher Pickle” 63 osteoclast osteoblast Lytic vs. Blastic lesions Kidney Thyroid Lung Above Ibone Prostate MIXED lytic & blastic Breast Lung University of Washington Radiology Case Reports 2015, pathologyoutlines.com 2015 64 37 What are risk factors for pathological fracture? Location - Peritrochanteric highest risk Size of lesion Lytic bone lesion Pain (bone) – functional (not attributable to disease) Higher Mirel’s score - above 9 = surgical fixation Radiation to bone Radiological imaging Axial Cortical Involvement (ACI) > 30 mm Circumferential Cortical Involvement (CCI) > 30% Scores range from 4 – 12 Nguyen et al. Cancers (Basel) 2021 qt surgery Fidler M. Incidence of fracture through metastases in long bones. Acta Orthop Scand. 1981;52:623–627. Van der Linden YM, Dijkstra PDS, Kroon HM, et al. Comparative analysis of risk factors for pathological fracture with femoral metastases. J. Bone Jt. Surg. Br. 2004, 86, 566–573. Tatar Z, Soubrier M, Dillies AF, et al. Assessment of the risk factors for impending fractures following radiotherapy for long bone metastases using CT scan-based virtual simulation: A retrospective study. Radiat. Oncol. 2014, 9, 227. Nguyễn MV, Carlier C, Nich C, Gouin F, Crenn V. Fracture Risk of Long Bone Metastases: A Review of Current and New Decision-Making Tools for Prophylactic Surgery. Cancers (Basel). 2021 Jul 21;13(15):3662. 65 PA Clinical Presentations/Red Flags When do I start to suspect that my patient is not here for a musculoskeletal, neuromuscular injury, or movement problem? Clinical presentations & red flags mom scone BLT with Mayo 9 t Surgery t kosher pickle 66 Capozza SJ. ‘Patient Is Otherwise Healthy’. JCO Oncol Pract 0, OP.23.00798 DOI:10.1200/OP.23.00798 “While we may be living clinically with no evidence of disease, we live with the evidence of the history of our disease every day. Like petrified trees or fossilized shells, cancer treatments leave permanent physical and psychological reminders of our cancer experience. As greater attention is being focused on the optimized management of long-term toxicities in cancer survivorship, my sincere hope is that there will be effort to educate cancer and noncancer medical staff alike about the real physical and psychosocial adverse effects as well as advances in treatment that will both prevent development of long-term toxicity and yield better solutions for when they do occur. I hope better options will be available to all cancer survivors with all stages and all disease types in the not so- distant future. I am OK, really, but I am not sure ‘otherwise healthy’ really applies to me.” Case Study radiation tissue fibrosis syndrome “Dropped Head Syndrome” Severe cervicothoracic malalignment Pt. Interview & History Subjective complaints of Shortness of breath Pain (8 - 10/10) & Fatigue (8/10) Unable to independently bathe, brush & style hair, reach overhead, etc Retired; married w/ supportive spouse, lives 50 miles away got Tests & Measures 82% O2 saturation Poor muscle strength Observation & Skin Inspection Posture blocking tracheostomy tube Severe radiation scarring Severe ant. neck shortening & posterior lengthening & muscle disuse atrophy Abnormal skin sensation & texture changes From: Appels C, Goekoop R. 2009. weakness inactivty posture EMERGENCY NECK BRACING Drain JP, et al 2019. Martin SR, et al. 2011. Appels C, Goekoop R. 2009. malarguan After 1 month of: Weekly Physical Therapy HEP & progression 2 monthly methotrexate treatments Still using supplemental O2 90% O2 Uses neck brace as needed Mostly at night After 6 months of: Weekly Physical Therapy HEP progression 8 monthly methotrexate treatments 92 – 95% O2 Uses brace as needed After 8 months of: Weekly Physical Therapy 10 monthly methotrexate treatments Hospitalized 1 week for pneumonia 95% O2 at rest Supplemental O2 at night & during exercise

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