# Lecture 14: Oncology Principles ## Unit 2.9: Hematology/Oncology --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Describe the principles of cancer biology and carcinogenesis 2. Explain cancer staging and performance status 3. Describe the principles of chemotherapy and targeted therapy 4. Explain immunotherapy and its mechanisms 5. Describe supportive care in oncology 6. Explain oncologic emergencies --- ## Lecture Outline ### I. Cancer Biology The hallmarks of cancer, as articulated by Hanahan and Weinberg, describe the core capabilities that normal cells must acquire during malignant transformation, providing a conceptual framework for understanding cancer biology. Sustained proliferative signaling allows cancer cells to maintain growth factor independence, generating their own mitogenic signals or becoming hypersensitive to exogenous growth factors rather than relying on external stimulation. Evading growth suppressors involves inactivation of tumor suppressor pathways such as the retinoblastoma and p53 pathways that normally restrain cell division. Resisting cell death enables cancer cells to evade apoptosis, the programmed cell death pathway that eliminates damaged or abnormal cells, allowing them to survive despite accumulating genetic damage. Enabling replicative immortality occurs through telomerase activation, which maintains telomere length and prevents the replicative senescence that limits normal cell division. Inducing angiogenesis stimulates new blood vessel formation to supply the growing tumor with oxygen and nutrients. Activating invasion and metastasis enables cancer cells to spread to distant sites through a complex multistep process. Deregulating cellular energetics involves metabolic reprogramming to support rapid proliferation, including the Warburg effect of aerobic glycolysis. Avoiding immune destruction allows tumors to evade recognition and killing by the immune system through multiple mechanisms. Oncogenes are mutated or overexpressed forms of normal cellular genes (proto-oncogenes) that drive cancer cell proliferation through gain-of-function mechanisms, acting in a genetically dominant fashion such that mutation of a single allele is sufficient to promote malignant transformation. HER2 amplification drives breast cancer through excessive growth factor receptor signaling. The BCR-ABL fusion gene, created by the Philadelphia chromosome translocation, produces a constitutively active tyrosine kinase that drives chronic myeloid leukemia. KRAS mutations are found in colon, lung, and pancreatic cancers, activating the RAS-MAPK proliferative signaling pathway. MYC overexpression, particularly from the translocation characteristic of Burkitt lymphoma, drives cell cycle progression and proliferation. BRAF V600E mutation activates the MAP kinase pathway in melanoma and other cancers. The gain-of-function nature of oncogene activation means that a single mutant allele confers the proliferative advantage, distinguishing oncogenes from tumor suppressors that require biallelic loss. Tumor suppressor genes normally function as brakes on cell proliferation, and their inactivation through loss-of-function mutations removes growth constraints and contributes to malignant transformation. TP53, encoding the p53 protein known as the "guardian of the genome," is the most commonly mutated gene in human cancers, normally functioning to arrest the cell cycle and induce apoptosis in response to DNA damage. RB1 encodes the retinoblastoma protein that controls the G1-to-S phase cell cycle transition, and its inactivation was the first tumor suppressor identified through studies of childhood retinoblastoma. BRCA1 and BRCA2 are involved in homologous recombination DNA repair, and their germline mutations confer substantially increased risk of breast and ovarian cancer. APC mutation initiates the adenoma-to-carcinoma sequence in colorectal cancer by activating the Wnt signaling pathway. VHL inactivation in renal cell carcinoma leads to stabilization of hypoxia-inducible factor and increased angiogenesis. Tumor suppressor inactivation follows the two-hit model described by Knudson, requiring loss of both alleles for complete functional elimination, with inherited cancer syndromes arising when one hit is inherited in the germline and the second occurs somatically. The process of carcinogenesis proceeds through defined stages reflecting the progressive accumulation of genetic and epigenetic alterations that transform a normal cell into a malignant one. Initiation involves DNA damage that creates a permanent mutation in a critical gene, potentially from environmental carcinogens, radiation, viral integration, or spontaneous replication errors. Promotion involves clonal expansion of the initiated cell through selective growth advantage, driven by factors that stimulate proliferation without directly damaging DNA, producing a population of pre-malignant cells. Progression encompasses the acquisition of additional mutations that confer the hallmark capabilities of cancer including invasiveness and metastatic potential, transforming a localized neoplasm into one capable of aggressive behavior. Metastasis, the spread of cancer to distant organs, is the ultimate stage and represents the primary cause of cancer mortality, involving a complex cascade of detachment from the primary tumor, invasion through basement membrane, intravasation into blood or lymphatic vessels, survival in circulation, extravasation at distant sites, and establishment of secondary colonies. Panel A: Hanahan and Weinberg hallmarks of cancer diagram showing sustained proliferation, evading growth suppression, resisting cell death, enabling immortality, inducing angiogenesis, and activating invasion. Panel B: Oncogene activation mechanisms including gene amplification, chromosomal translocation, and point mutation resulting in gain of function. Panel C: Tumor suppressor gene inactivation through two-hit model with inherited or somatic first hit followed by loss of heterozygosity. Panel D: Carcinogenesis stages from initiation through promotion to progression and metastasis with accumulating genetic alterations. --- ### II. Staging and Classification The TNM staging system provides a standardized framework for classifying the anatomic extent of cancer, serving as the foundation for treatment planning, prognostic assessment, and communication among clinicians and researchers. The T component describes the primary tumor's size and extent of local invasion, with higher numbers indicating larger or more locally advanced disease. The N component describes the extent of regional lymph node involvement, ranging from no nodal disease to extensive regional node metastases. The M component indicates whether distant metastases are present (M1) or absent (M0), with metastatic disease fundamentally altering prognosis and treatment approach. These three components are combined into an overall stage grouping from I through IV, where stage I represents localized, small tumors, stage II indicates larger tumors or minimal lymph node involvement, stage III signifies locally advanced disease or significant regional nodal spread, and stage IV denotes the presence of distant metastases. Performance status assessment quantifies the patient's overall functional capacity and is one of the most important factors in determining treatment tolerance and prognosis. The Eastern Cooperative Oncology Group (ECOG) scale uses a simple 0 to 4 grading system that is widely used in clinical practice and research. ECOG 0 indicates a fully active patient with no functional limitations. ECOG 1 describes a patient restricted in strenuous physical activity but ambulatory and able to carry out light work. ECOG 2 indicates a patient who is ambulatory and capable of all self-care but unable to carry out work activities, spending less than 50 percent of waking hours in bed. ECOG 3 describes a patient capable of only limited self-care who spends more than 50 percent of waking hours in bed or chair. ECOG 4 indicates a completely disabled patient confined to bed or chair who cannot perform any self-care. Performance status is critically important because it determines treatment tolerance, with poor performance status patients generally unable to tolerate aggressive chemotherapy and having worse outcomes regardless of treatment. The Karnofsky Performance Status scale provides a more granular assessment of functional capacity using a 100-point scale that predates the ECOG system and remains in use, particularly in certain clinical trial settings and specialty areas. A score of 100 indicates a normal patient with no complaints and no evidence of disease. Scores of 80 to 90 reflect patients with minor signs or symptoms who are able to carry on normal activity. Scores of 60 to 70 describe patients who require occasional assistance but are able to care for most of their own needs. Scores of 40 to 50 indicate patients who require considerable assistance and frequent medical care. Scores of 20 to 30 reflect severely disabled patients who require hospitalization. A score of 10 indicates a moribund patient approaching death. The Karnofsky and ECOG scales correlate well with each other and both serve as independent prognostic factors across cancer types. Tumor markers are substances produced by cancer cells or by the body in response to cancer that can be measured in blood, urine, or tissue, serving roles in diagnosis, treatment monitoring, and recurrence detection. Prostate-specific antigen (PSA) is used in prostate cancer detection and monitoring. Carcinoembryonic antigen (CEA) is elevated in colorectal and other gastrointestinal cancers. Alpha-fetoprotein (AFP) is used for hepatocellular carcinoma and germ cell tumors. CA-125 is elevated in ovarian cancer and monitored for treatment response and recurrence. CA 19-9 is associated with pancreatic cancer. Beta-human chorionic gonadotropin (beta-hCG) is elevated in germ cell tumors and choriocarcinoma. An important principle is that tumor markers are generally most useful for monitoring treatment response and detecting recurrence rather than for primary screening or diagnosis, as they often lack the sensitivity and specificity required for population-level screening and may be elevated in benign conditions. Panel A: TNM staging system components with T indicating primary tumor size and extent, N for regional lymph node involvement, and M for distant metastases. Panel B: Stage grouping from I localized through II-III locally advanced to IV metastatic with general prognostic implications. Panel C: ECOG performance status scale from 0 fully active through 4 completely disabled with treatment tolerance predictions. Panel D: Karnofsky performance scale comparison from 100% normal to 10% moribund with corresponding functional descriptions. --- ### III. Principles of Chemotherapy The goals of chemotherapy treatment are defined by the clinical context and disease stage, with fundamentally different treatment intents guiding the aggressiveness and duration of therapy. Curative intent aims to achieve complete remission and long-term disease eradication, as seen in the treatment of testicular cancer, acute leukemia, and Hodgkin lymphoma, where the toxicity of aggressive therapy is justified by the realistic expectation of cure. Adjuvant therapy is administered after definitive surgical resection to eliminate microscopic residual disease (micrometastases) that may be present but undetectable, reducing the risk of distant recurrence and improving survival as demonstrated in breast and colorectal cancer. Neoadjuvant therapy is given before surgery to shrink the primary tumor, potentially enabling less extensive surgical resection, providing information about tumor chemosensitivity, and addressing micrometastatic disease early. Palliative chemotherapy aims to control symptoms, improve quality of life, and prolong survival in patients with incurable metastatic disease, where the balance between therapeutic benefit and treatment-related toxicity becomes the central consideration. The relationship between the cell cycle and chemotherapy underpins the rational design of treatment regimens and the selection of drug combinations. During G1 phase, cells are preparing for DNA synthesis and are susceptible to agents such as asparaginase that deplete essential amino acids. S phase, when DNA replication occurs, is the target of antimetabolites that incorporate into or interfere with DNA synthesis. G2 and M phases, when cells prepare for and undergo mitosis, are targeted by microtubule-directed agents including vinca alkaloids that inhibit spindle formation and taxanes that prevent spindle disassembly. Cell cycle-nonspecific agents including alkylating agents and anthracyclines damage DNA regardless of the cell's position in the cell cycle, exerting their effects on both dividing and resting cells. This understanding of cell cycle specificity informs treatment scheduling, with cycle-specific agents often benefiting from prolonged exposure and non-specific agents effective as bolus doses. The major classes of cytotoxic chemotherapy agents each have distinct mechanisms of action, toxicity profiles, and clinical applications. Alkylating agents including cyclophosphamide and cisplatin form covalent bonds with DNA bases creating cross-links that prevent DNA strand separation during replication. Antimetabolites such as methotrexate, 5-fluorouracil, and cytarabine structurally resemble normal cellular metabolites and interfere with DNA or RNA synthesis by competing with or substituting for natural substrates. Anthracyclines, exemplified by doxorubicin, intercalate between DNA base pairs and inhibit topoisomerase II, generating DNA strand breaks, with cumulative cardiac toxicity being a characteristic dose-limiting side effect. Vinca alkaloids including vincristine and vinblastine bind tubulin and inhibit microtubule polymerization, preventing mitotic spindle formation and arresting cells in mitosis. Taxanes such as paclitaxel and docetaxel work through the opposite mechanism, stabilizing microtubules and preventing their depolymerization, which is equally lethal to dividing cells. Topoisomerase inhibitors including irinotecan (topoisomerase I) and etoposide (topoisomerase II) stabilize the enzyme-DNA complex, creating persistent DNA strand breaks that trigger apoptosis. Combination chemotherapy, the simultaneous or sequential administration of multiple drugs, is a foundational principle of cancer treatment based on several key rationales. Using drugs with different mechanisms of action attacks cancer cells through multiple pathways simultaneously, reducing the probability that any single resistance mechanism will allow tumor survival. Selecting agents with non-overlapping toxicity profiles allows each drug to be administered at or near its full effective dose without intolerable cumulative side effects on any single organ system. Drug combinations often demonstrate synergistic activity, producing greater cell kill than would be predicted by the additive effects of individual agents. Combining drugs with different resistance mechanisms helps prevent the emergence of resistant clones, as a cell that develops resistance to one drug remains susceptible to the others in the regimen. Panel A: Cell cycle diagram showing G1, S, G2, and M phases with phase-specific drug targets including antimetabolites in S phase and vinca alkaloids in M phase. Panel B: Chemotherapy drug class mechanisms including alkylating agent DNA crosslinking, antimetabolite synthesis inhibition, and anthracycline DNA intercalation. Panel C: Microtubule-targeting agents showing vinca alkaloid inhibition of polymerization versus taxane inhibition of depolymerization. Panel D: Combination chemotherapy principles with different mechanisms, non-overlapping toxicities, synergistic activity, and resistance prevention. --- ### IV. Targeted Therapy Targeted therapy represents a paradigm shift from conventional cytotoxic chemotherapy, using agents designed to interfere with specific molecular targets that drive cancer cell growth, proliferation, and survival. Tyrosine kinase inhibitors are small molecules that block the enzymatic activity of specific kinases, with imatinib targeting BCR-ABL in CML and erlotinib targeting EGFR in lung cancer as landmark examples. Monoclonal antibodies are large protein molecules engineered to bind specific extracellular targets, with trastuzumab targeting HER2 in breast cancer and rituximab targeting CD20 on B-cell lymphomas. Proteasome inhibitors such as bortezomib disrupt protein degradation pathways critical for myeloma cell survival. mTOR inhibitors including everolimus block the mammalian target of rapamycin signaling pathway involved in cell growth regulation. CDK inhibitors such as palbociclib target cyclin-dependent kinases that regulate cell cycle progression. PARP inhibitors including olaparib exploit defective DNA repair mechanisms in BRCA-mutated cancers through the concept of synthetic lethality. The clinical impact of targeted therapy is best illustrated through landmark drug-target-disease combinations that have transformed outcomes. Imatinib targeting BCR-ABL converted chronic myeloid leukemia from a fatal disease to a chronic manageable condition with near-normal life expectancy. Trastuzumab targeting HER2-amplified breast cancer significantly improved survival in a subset of aggressive breast cancers that previously had among the worst prognoses. Rituximab targeting CD20 on B-cell lymphomas revolutionized the treatment of non-Hodgkin lymphoma and became the first monoclonal antibody widely used in oncology. Vemurafenib targeting BRAF V600E mutation produces rapid responses in melanoma harboring this specific mutation. Erlotinib and other EGFR inhibitors have transformed the treatment of EGFR-mutant non-small cell lung cancer, with response rates far exceeding those of conventional chemotherapy. Bevacizumab targeting vascular endothelial growth factor (VEGF) inhibits tumor angiogenesis and has demonstrated benefit in colorectal cancer and other malignancies. Molecular testing is essential for the rational application of targeted therapy, as treatment selection depends on identifying the specific molecular alterations driving each patient's cancer. Next-generation sequencing (NGS) panels simultaneously analyze hundreds of genes to identify actionable mutations that can be targeted with available therapies. Fluorescence in situ hybridization (FISH) detects gene amplifications such as HER2 and chromosomal translocations such as ALK fusions that direct specific treatment selection. Immunohistochemistry (IHC) assesses protein expression levels in tumor tissue, providing a practical and widely available method for biomarker assessment. Circulating tumor DNA (ctDNA) analysis from blood samples, known as liquid biopsy, enables non-invasive molecular profiling and monitoring of treatment response and resistance evolution. Tumor mutational burden, reflecting the total number of somatic mutations in a tumor, has emerged as a predictor of immunotherapy response across cancer types. Resistance to targeted therapy is an inevitable challenge that limits the durability of responses and drives disease progression in the majority of patients. Secondary mutations within the drug target represent a common resistance mechanism, exemplified by the T790M mutation in EGFR that confers resistance to first-generation EGFR inhibitors by altering the drug binding site. Activation of alternative signaling pathways allows cancer cells to bypass the inhibited target by rewiring their growth and survival signals through parallel routes. Drug efflux mediated by P-glycoprotein and related transporters actively pumps targeted agents out of cancer cells, reducing intracellular drug concentrations below therapeutic levels. Tumor heterogeneity, where the cancer contains a mixture of molecularly distinct clonal populations, enables selection and outgrowth of pre-existing resistant subclones under the selective pressure of targeted therapy. Panel A: Tyrosine kinase inhibitor mechanism showing small molecule blocking ATP binding site of oncogenic kinase such as BCR-ABL or EGFR. Panel B: Monoclonal antibody mechanisms including receptor blockade, antibody-dependent cellular cytotoxicity, and complement activation. Panel C: Molecular testing methods including next-generation sequencing for mutations, FISH for amplifications and translocations, and immunohistochemistry for protein expression. Panel D: Resistance mechanisms showing secondary mutations bypassing inhibition, alternative pathway activation, and drug efflux pumps. --- ### V. Immunotherapy Immune checkpoint inhibitors have revolutionized cancer treatment by harnessing the patient's own immune system to recognize and destroy cancer cells, representing a fundamentally different approach from cytotoxic chemotherapy and targeted therapy. Antibodies targeting PD-1, including pembrolizumab and nivolumab, block the interaction between PD-1 on T cells and its ligands on tumor cells, preventing the T-cell exhaustion that allows tumors to evade immune destruction. Anti-PD-L1 antibodies including atezolizumab and durvalumab achieve the same effect by targeting the ligand on the tumor cell side of the interaction. Ipilimumab targets CTLA-4, an earlier checkpoint in T-cell activation that normally dampens the immune response during the priming phase in lymph nodes. The fundamental mechanism of all checkpoint inhibitors is to release the brakes on T-cell activity, restoring the ability of tumor-specific T cells to recognize and kill cancer cells that had evaded immune surveillance. The clinical success of checkpoint inhibitors has expanded across a remarkable range of cancer types since the initial approval in melanoma. Melanoma was the first approved indication, where checkpoint inhibitors transformed a cancer with previously limited treatment options into one where durable long-term responses and potential cures are achievable. Non-small cell lung cancer responds to checkpoint inhibition particularly well when PD-L1 expression is high on tumor cells, with PD-L1 immunohistochemistry serving as a predictive biomarker for response. Renal cell carcinoma is treated with combinations of checkpoint inhibitors and tyrosine kinase inhibitors. Hodgkin lymphoma demonstrates particularly high response rates to PD-1 blockade due to genetic amplification of the PD-L1 locus. Tumors with high microsatellite instability (MSI-high) respond to pembrolizumab regardless of histologic type, leading to the first tissue-agnostic FDA approval in oncology based on a molecular biomarker rather than a specific cancer type. Immune-related adverse events represent a unique toxicity profile that distinguishes checkpoint inhibitors from conventional chemotherapy and reflects the mechanism of unleashing immune activity against not only tumor but also normal tissues. Dermatologic manifestations including rash and vitiligo are among the most common and earliest-presenting adverse events. Gastrointestinal toxicity manifests as colitis with diarrhea that may be severe and require immunosuppressive treatment. Hepatic inflammation presents as autoimmune hepatitis with elevated transaminases. Endocrine complications include thyroiditis that may cause transient hyperthyroidism followed by hypothyroidism, hypophysitis affecting the pituitary gland, and adrenal insufficiency. Pulmonary toxicity manifests as pneumonitis with dyspnea and bilateral infiltrates that can be life-threatening. Management of immune-related adverse events follows a graded approach: mild events may be monitored with continuation of immunotherapy, moderate events require holding immunotherapy and initiating systemic corticosteroids, and severe events necessitate permanent discontinuation of immunotherapy with high-dose steroids and potentially additional immunosuppressive agents. Beyond checkpoint inhibitors, several other immunotherapy modalities have demonstrated clinical efficacy in specific settings. Chimeric antigen receptor T-cell (CAR-T) therapy, including tisagenlecleucel and axicabtagene ciloleucel, involves engineering the patient's own T cells to express a receptor targeting tumor-specific antigens such as CD19 on B-cell malignancies, producing remarkable responses in refractory leukemia and lymphoma. Bispecific antibodies such as blinatumomab are engineered proteins that simultaneously bind a tumor antigen (CD19) and a T-cell receptor component (CD3), physically bridging T cells to cancer cells to facilitate killing. Cancer vaccines, exemplified by sipuleucel-T for prostate cancer, aim to stimulate the patient's immune system against tumor-associated antigens. Cytokine therapy using interleukin-2 (IL-2) and interferon was among the earliest immunotherapy approaches, demonstrating the potential for immune-mediated tumor regression though with significant toxicity. Panel A: Checkpoint inhibitor mechanism showing PD-1/PD-L1 and CTLA-4 blockade releasing T-cell brakes to enable tumor cell killing. Panel B: Immune-related adverse events by organ system including dermatitis, colitis, hepatitis, pneumonitis, and endocrinopathies. Panel C: irAE management algorithm with immunotherapy hold, steroid initiation, and escalation to additional immunosuppression if needed. Panel D: CAR-T cell therapy mechanism showing T-cell engineering with chimeric antigen receptor, expansion, and targeting of tumor-specific antigens like CD19. --- ### VI. Radiation Therapy Radiation therapy uses ionizing radiation to damage cancer cell DNA, primarily through the generation of double-strand breaks that overwhelm cellular repair mechanisms and trigger cell death. The principle of fractionation, delivering the total radiation dose in multiple small daily fractions rather than a single large dose, exploits the differential repair capacity between normal tissues and tumor cells, allowing normal tissues to recover between fractions while cumulative damage accumulates in less repair-proficient tumor cells. The total radiation dose is measured in Gray (Gy), with different tumor types and clinical settings requiring different total doses and fractionation schedules. Rapidly dividing cells are most sensitive to radiation because DNA damage is most lethal when encountered during DNA replication and mitosis, explaining why radiation is particularly effective against rapidly proliferating tumors and why rapidly dividing normal tissues such as mucosal epithelium and bone marrow are the most susceptible to radiation side effects. Multiple types of radiation therapy exist, each with distinct technical characteristics suited to specific clinical applications. External beam radiation therapy (EBRT) is delivered from a machine outside the body and represents the most common radiation modality. Three-dimensional conformal radiation therapy (3D-CRT) shapes radiation beams to conform to the tumor volume based on imaging. Intensity-modulated radiation therapy (IMRT) further refines beam delivery by varying the intensity across each beam, enabling superior dose conformality and improved sparing of adjacent normal structures. Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) deliver very high doses in a small number of fractions with extreme precision, used for small well-defined tumors including brain metastases and early-stage lung cancer. Brachytherapy involves placing a radioactive source directly within or adjacent to the tumor, delivering high local doses with rapid dose fall-off to spare surrounding tissues, commonly used in cervical, prostate, and endometrial cancers. Proton therapy uses charged particles that deposit most of their energy at a specific depth (the Bragg peak), reducing the exit dose beyond the tumor and potentially decreasing damage to distal normal tissues. The indications for radiation therapy span the full spectrum of treatment intent from curative to palliative. Curative radiation is used as definitive treatment for cancers of the prostate, head and neck, lung, and cervix, either alone or in combination with concurrent chemotherapy that enhances radiosensitivity. Adjuvant radiation following surgery reduces local recurrence risk in breast cancer after breast-conserving surgery and in rectal cancer following resection. Palliative radiation provides effective symptom relief for bone metastases causing pain, brain metastases causing neurologic symptoms, and obstructing tumors causing bleeding or compression. Consolidation radiation after chemotherapy is used in certain lymphomas to treat sites of bulky disease and reduce relapse risk. Side effects of radiation therapy are classified as acute, occurring during or shortly after treatment, and chronic, developing months to years later, with both categories determined by the anatomic region treated. Acute effects include skin erythema resembling sunburn in the treatment field, mucositis causing painful inflammation of mucosal surfaces when head, neck, or pelvic regions are treated, fatigue which is common across all treatment sites, diarrhea from pelvic irradiation damaging intestinal mucosa, and nausea when the abdomen or brain is treated. Chronic effects develop from progressive tissue fibrosis and vascular damage and include fibrosis causing tissue stiffness and functional impairment, xerostomia (dry mouth) from salivary gland damage in head and neck radiation, lymphedema from damage to lymphatic drainage, secondary malignancies developing in the irradiated field years to decades later, and cardiac toxicity from mediastinal irradiation that may manifest as accelerated coronary artery disease, valvular dysfunction, or pericardial disease. Panel A: External beam radiation therapy types from 3D-conformal through IMRT to SBRT with increasing precision and dose conformality. Panel B: Brachytherapy with radioactive source placement near tumor for cervical, prostate, and other localized cancers. Panel C: Dose-volume histogram showing tumor coverage and organ-at-risk sparing with treatment planning optimization. Panel D: Acute and late radiation side effects including skin erythema and mucositis acutely versus fibrosis and secondary malignancy risk long-term. --- ### VII. Supportive Care Chemotherapy-induced nausea and vomiting is one of the most distressing side effects of cancer treatment and requires proactive, risk-stratified antiemetic prophylaxis based on the emetogenic potential of the chemotherapy regimen. High emetogenic risk regimens such as cisplatin require triple antiemetic therapy combining a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone, administered before chemotherapy and continued for several days afterward. Moderate emetogenic risk regimens are typically managed with a 5-HT3 antagonist combined with dexamethasone. Low emetogenic risk regimens may require only a single antiemetic agent or as-needed medications. The specific agents commonly used include ondansetron (a 5-HT3 antagonist that blocks serotonin receptors in the chemoreceptor trigger zone and gut), aprepitant (an NK1 antagonist that blocks substance P-mediated delayed emesis), and dexamethasone (a corticosteroid with antiemetic properties through incompletely understood mechanisms). Febrile neutropenia is an oncologic emergency defined as an absolute neutrophil count below 500 per microliter accompanied by a fever of 38.3 degrees Celsius or higher, requiring immediate evaluation and empiric broad-spectrum antibiotic therapy because infection can progress to sepsis and death within hours in the absence of effective neutrophil-mediated immune defense. Management begins with prompt administration of empiric antibiotics covering gram-negative organisms including Pseudomonas, typically with an antipseudomonal beta-lactam, before culture results are available. Granulocyte colony-stimulating factor (G-CSF) is used for both primary prophylaxis in patients receiving regimens with a high risk of febrile neutropenia and secondary prophylaxis following an episode of febrile neutropenia to reduce the risk of recurrence in subsequent cycles. Risk assessment tools such as the MASCC score help identify patients who may be suitable for outpatient management with oral antibiotics, reserving hospitalization for higher-risk patients. Cancer pain management follows the WHO analgesic ladder, a stepwise approach that escalates treatment based on pain severity. Step 1 uses non-opioid analgesics including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) for mild pain. Step 2 introduces weak opioids or low-dose strong opioids for moderate pain not controlled by non-opioid agents alone. Step 3 employs strong opioids such as morphine, oxycodone, or fentanyl for severe pain. Adjuvant medications are used at any step to address specific pain types, with neuropathic pain responding to gabapentin and duloxetine, which target the altered nerve signaling responsible for burning, shooting, and tingling pain qualities. Bone pain from metastatic disease benefits from targeted approaches including palliative radiation therapy to painful sites and bisphosphonates or denosumab to inhibit osteoclast-mediated bone destruction. Supportive care in oncology extends beyond nausea and pain to address the full spectrum of treatment-related and disease-related symptoms that impair quality of life. Cancer-related fatigue is the most commonly reported symptom and is managed by addressing correctable contributing factors such as anemia, hypothyroidism, and depression, along with structured exercise programs that have demonstrated consistent benefit. Anemia may be treated with erythropoiesis-stimulating agents in selected patients or with red blood cell transfusion for more severe cases. Mucositis from chemotherapy-induced mucosal injury causes painful oral ulceration managed with meticulous oral care, topical anesthetics, and combination mouthwashes. Chemotherapy-induced diarrhea is treated with loperamide as first-line therapy, with octreotide reserved for severe or refractory cases. Cancer cachexia, the progressive weight loss and muscle wasting that accompanies advanced malignancy, is addressed through nutritional support and appetite stimulants, though it remains one of the most challenging supportive care problems in oncology. Panel A: Antiemetic algorithm stratified by chemotherapy emetogenic risk with 5-HT3, NK1, and dexamethasone combinations for high-risk regimens. Panel B: WHO pain ladder from non-opioid analgesics through weak opioids to strong opioids with adjuvant medications at each step. Panel C: Febrile neutropenia protocol with immediate broad-spectrum antibiotic initiation, blood cultures, and risk assessment for inpatient versus outpatient management. Panel D: G-CSF prophylaxis indications based on regimen intensity and patient risk factors to prevent severe neutropenia. --- ### VIII. Oncologic Emergencies Tumor lysis syndrome is a potentially fatal metabolic emergency that occurs when rapid destruction of tumor cells releases intracellular contents into the bloodstream faster than the body can metabolize and excrete them. Hyperuricemia results from the breakdown of nucleic acids to uric acid, which can precipitate in the renal tubules causing uric acid nephropathy and acute kidney injury. Hyperkalemia from release of intracellular potassium poses an immediate risk of fatal cardiac arrhythmias. Hyperphosphatemia from release of intracellular phosphate binds circulating calcium causing secondary hypocalcemia, which can produce tetany, seizures, and cardiac dysfunction. Prevention is the cornerstone of management and includes aggressive intravenous hydration to maintain high urine output, allopurinol to block xanthine oxidase and reduce uric acid production, and rasburicase (recombinant urate oxidase) for patients at highest risk to rapidly enzymatically degrade existing uric acid. Treatment of established tumor lysis requires aggressive fluid resuscitation, correction of electrolyte abnormalities, and occasionally dialysis for severe renal failure or refractory hyperkalemia. Malignant spinal cord compression represents a neurologic emergency where metastatic tumor in the epidural space compresses the spinal cord, threatening irreversible neurologic damage. The clinical presentation typically begins with progressive back pain that may be worse at night or with recumbency, followed by neurologic deficits including lower extremity weakness, a sensory level below which sensation is diminished, and bowel or bladder incontinence indicating autonomic involvement. The urgency of this condition lies in preserving neurologic function, as the ambulatory status at the time of diagnosis is the strongest predictor of functional outcome after treatment. Diagnosis requires urgent MRI of the entire spine, as multiple levels of compression may be present. Treatment begins with immediate high-dose corticosteroids to reduce peritumoral edema, followed by radiation therapy as the primary treatment for most cases, with surgical decompression considered when there is structural instability, radioresistant tumor histology, or neurologic deterioration during radiation. Superior vena cava syndrome results from obstruction of blood flow through the superior vena cava, most commonly caused by external compression from a mediastinal tumor or less frequently by intraluminal thrombosis. Symptoms develop from impaired venous drainage of the head, neck, and upper extremities and include facial swelling and plethora, dyspnea from airway edema and pleural effusions, and distension of neck and chest wall veins. The most common underlying cancers are lung cancer and lymphoma, which together account for the vast majority of malignant cases. Treatment depends on the underlying cause and includes radiation therapy for radiosensitive tumors, chemotherapy particularly for lymphoma and small cell lung cancer, endovascular stenting for rapid symptom relief, and thrombolytic therapy when thrombosis contributes to the obstruction. Importantly, SVC syndrome is not always a true emergency unless airway compromise is present, and in many cases tissue diagnosis should be obtained before initiating treatment to guide appropriate therapy. Hypercalcemia of malignancy is the most common metabolic emergency in cancer patients and occurs through several distinct pathophysiologic mechanisms. Secretion of parathyroid hormone-related peptide (PTHrP) by tumor cells is the most common mechanism, mimicking the calcium-mobilizing effects of parathyroid hormone on bone and kidney without the regulatory feedback that controls normal PTH secretion. Osteolytic metastases, particularly from breast cancer and multiple myeloma, directly destroy bone and release calcium into the circulation through local cytokine-mediated osteoclast activation. Production of 1,25-dihydroxyvitamin D by lymphoma cells causes increased intestinal calcium absorption. Treatment begins with aggressive intravenous normal saline hydration to restore intravascular volume and promote renal calcium excretion. Bisphosphonates such as zoledronic acid inhibit osteoclast-mediated bone resorption and are the mainstay of treatment, though their effect takes 2 to 4 days to manifest fully. Denosumab, a RANKL inhibitor, provides an alternative anti-resorptive approach. Calcitonin produces a rapid but transient reduction in calcium levels and is useful as a bridge while awaiting the onset of bisphosphonate effect. Panel A: Tumor lysis syndrome metabolic derangements with hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia with prevention using hydration, allopurinol, and rasburicase. Panel B: Spinal cord compression MRI showing epidural tumor mass with cord displacement requiring urgent steroids and radiation or surgical decompression. Panel C: Superior vena cava syndrome with facial swelling, venous distension, and dyspnea from mediastinal tumor compression treated with radiation, chemotherapy, or stenting. Panel D: Hypercalcemia of malignancy from PTHrP or osteolytic metastases treated with fluids, bisphosphonates, and denosumab. --- ### IX. Special Topics Cancer survivorship addresses the unique medical, psychosocial, and practical needs of the growing population of patients who have completed cancer treatment and are living beyond their diagnosis. Surveillance for cancer recurrence follows evidence-based schedules specific to each cancer type, combining clinical examination, imaging, and laboratory monitoring at intervals determined by the risk and timing of recurrence. Late effects of cancer treatment may manifest years to decades after therapy and include cardiac dysfunction from anthracycline chemotherapy or mediastinal radiation, secondary malignancies in radiation fields or from alkylating agent exposure, and fertility impairment from gonadotoxic treatments. Psychosocial challenges are substantial and include depression, anxiety, fear of recurrence that may be debilitating, and difficulties with reintegration into work and social roles. Health maintenance including age-appropriate vaccinations, lifestyle counseling regarding exercise and nutrition, and screening for late treatment effects forms an essential component of survivorship care. Survivorship care plans that document the treatment received, anticipated late effects, and recommended surveillance schedule provide a framework for coordinating ongoing care between oncologists and primary care providers. Fertility preservation must be discussed with all patients of reproductive age before initiating gonadotoxic therapy, as many chemotherapy regimens and radiation fields can cause permanent infertility. Female patients have options including oocyte cryopreservation (egg freezing), embryo cryopreservation for those with a partner, and investigational ovarian tissue cryopreservation. Male patients can undergo sperm banking, a relatively simple and widely available option that should be offered to all male patients before treatment. Timing is critical, as fertility preservation procedures must be completed before the initiation of gonadotoxic chemotherapy or radiation, requiring prompt referral to a reproductive endocrinologist at the time of cancer diagnosis. Palliative care focuses on quality of life and symptom management for patients with serious illness and should be integrated early in the disease course rather than reserved for end-of-life care. The focus encompasses expert symptom management, psychosocial support, assistance with complex medical decision-making, and coordination of care across settings. Early integration of palliative care has been demonstrated to improve quality of life, reduce symptom burden, decrease healthcare utilization, and in some studies extend overall survival. Hospice care is a specific form of palliative care for patients with an estimated prognosis of less than 6 months who have chosen to focus on comfort rather than disease-directed treatment. Goals of care discussions should be ongoing throughout the disease trajectory, helping patients articulate their values and preferences as clinical circumstances evolve. Clinical trials represent the mechanism through which new cancer treatments are developed, tested, and brought to patient care, following a structured phase system. Phase I trials focus on safety and dose-finding, establishing the maximum tolerated dose and characterizing the side effect profile of a new agent in a small number of patients. Phase II trials evaluate efficacy and further characterize side effects in a larger patient population, providing initial evidence of whether the treatment produces meaningful clinical responses. Phase III trials compare the new treatment against the current standard of care in large randomized studies, providing the definitive evidence needed for regulatory approval. Phase IV trials, conducted after regulatory approval, monitor long-term safety and effectiveness in the post-marketing setting. Clinical trials are critically important because they provide patients access to new and potentially more effective therapies while generating the evidence base that advances cancer treatment for future patients. Panel A: Late effects surveillance including cardiac monitoring after anthracyclines, pulmonary function after bleomycin, and secondary malignancy screening. Panel B: Survivorship care plan elements documenting treatment received, surveillance schedule, late effect risks, and health maintenance recommendations. Panel C: Palliative care integration early in disease course improving quality of life, symptom management, and goals of care discussions. Panel D: Fertility preservation options including sperm banking and oocyte cryopreservation discussed before gonadotoxic therapy initiation. --- ### X. Precision Medicine Molecular profiling has become the foundation of modern cancer treatment, enabling identification of specific genetic alterations that drive individual tumors and can be targeted with available therapies. Next-generation sequencing panels analyze hundreds of genes simultaneously from tumor tissue, identifying actionable mutations, amplifications, fusions, and other alterations that inform treatment selection. RNA sequencing reveals gene expression patterns that classify tumors into molecular subtypes with distinct biology and treatment sensitivity. Whole exome sequencing provides comprehensive mutation analysis across all protein-coding genes, enabling discovery of novel alterations and assessment of overall tumor mutational burden. Liquid biopsy using circulating tumor DNA (ctDNA) from blood samples enables non-invasive molecular profiling, real-time monitoring of treatment response, early detection of resistance mutations, and assessment of minimal residual disease without requiring repeated tissue biopsies. Biomarker-driven treatment selection represents the practical application of precision medicine, matching specific molecular alterations to targeted therapies with demonstrated efficacy against those alterations. EGFR mutations in non-small cell lung cancer are treated with osimertinib, a third-generation EGFR inhibitor with activity against both sensitizing mutations and the T790M resistance mutation. ALK gene fusions are treated with alectinib and other ALK inhibitors that produce dramatic responses in ALK-rearranged lung cancers. HER2 amplification in breast cancer directs treatment with trastuzumab and other HER2-targeted agents. BRCA1 and BRCA2 mutations in ovarian and breast cancer identify patients who benefit from PARP inhibitors that exploit the defective DNA repair pathway through synthetic lethality. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors are treated with pembrolizumab regardless of cancer type. NTRK gene fusions are treated with larotrectinib, another tissue-agnostic approval based on molecular alteration rather than histologic diagnosis. Tumor-agnostic approvals represent a fundamental paradigm shift in oncology, basing treatment selection on the molecular features of the tumor rather than the organ of origin. The concept recognizes that tumors from different anatomic sites sharing the same molecular driver may respond to the same targeted therapy, regardless of their tissue of origin. The approval of pembrolizumab for MSI-high tumors was a landmark event, establishing that a biomarker present across many cancer types could serve as the basis for treatment selection independently of histology. Similarly, the approval of larotrectinib for NTRK fusion-positive tumors demonstrated high response rates across a wide variety of cancer types harboring this rare but druggable alteration. This tissue-agnostic treatment paradigm represents a conceptual shift from treating "cancer of organ X" to treating "cancer driven by molecular alteration Y," with profound implications for how clinical trials are designed, drugs are developed, and patients are treated. Future directions in oncology encompass multiple innovative approaches that promise to further expand treatment options and improve outcomes. Personalized cancer vaccines based on tumor-specific neoantigens aim to stimulate highly targeted immune responses against the unique mutations present in each patient's tumor. Combination immunotherapy targeting multiple checkpoint pathways simultaneously seeks to overcome resistance mechanisms that limit single-agent checkpoint blockade. Extension of CAR-T cell therapy from hematologic malignancies to solid tumors faces challenges including identifying suitable target antigens, overcoming the immunosuppressive tumor microenvironment, and improving T-cell trafficking to solid tumor sites. Bispecific antibodies that engage T cells against tumor targets are expanding beyond CD19-directed blinatumomab to target a growing array of tumor antigens. Antibody-drug conjugate (ADC) development is expanding to new targets, combining the specificity of antibody-mediated delivery with the potency of cytotoxic payloads to create a rapidly growing class of precision therapeutics. Panel A: Molecular profiling workflow from tumor biopsy through next-generation sequencing to actionable mutation identification and targeted therapy selection. Panel B: Biomarker-treatment matching examples including EGFR mutation with osimertinib, ALK fusion with alectinib, and BRCA mutation with PARP inhibitors. Panel C: Tissue-agnostic approvals for pembrolizumab in MSI-high tumors and larotrectinib in NTRK fusion-positive cancers regardless of histology. Panel D: Future directions including personalized neoantigen vaccines, combination immunotherapy, and CAR-T expansion to solid tumors. --- ## Summary - Hallmarks of cancer: Proliferation, immune evasion, angiogenesis, invasion - Staging: TNM system; performance status guides treatment decisions - Chemotherapy: Cell cycle targeting; combination therapy for synergy - Targeted therapy: Attack specific molecular drivers (EGFR, HER2, BRAF) - Immunotherapy: Checkpoint inhibitors release T-cell brakes; irAEs important - Radiation: DNA damage; fractionation; curative or palliative - Supportive care: Antiemetics, febrile neutropenia, pain management - Oncologic emergencies: TLS, cord compression, SVC syndrome, hypercalcemia - Precision medicine: Molecular profiling drives treatment selection - Survivorship: Address late effects, second cancers, psychosocial needs --- ## Key Terms | Term | Definition | |------|------------| | Hallmarks of cancer | Core capabilities enabling tumor growth and spread | | TNM staging | Tumor, Node, Metastasis classification | | Adjuvant therapy | Treatment after surgery to prevent recurrence | | Targeted therapy | Drugs attacking specific molecular targets | | Checkpoint inhibitor | Immunotherapy releasing T-cell brakes | | irAE | Immune-related adverse event | | TLS | Tumor lysis syndrome | | Precision medicine | Treatment based on individual tumor molecular profile | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*