Principles of Anti-Cancer Therapy PDF

💊 PG 3 Date @November 18, 2024 Status Done Topic principles of anti-cancer therapy Principles of anti-cancer therapy The ideal standard therapy would be one that cures everyone without causing adverse events. This is a goal...

💊 PG 3 Date @November 18, 2024 Status Done Topic principles of anti-cancer therapy Principles of anti-cancer therapy The ideal standard therapy would be one that cures everyone without causing adverse events. This is a goal that we are still far from achieving. For any treatment, there is always room for improvement whether it is reducing the intensity or duration of therapy, which would minimize side effects, improve quality of life, and shorten treatment times. This is why clinical trials are normal and integral parts of standard patient care. In fact, there are clinical trials even for first-line therapies. The pillars of therapy in oncology surgery radiotherapy chemotherapy immunotherapy target therapies this is gradually replacing chemotherapy it’s aim is not to cure cancer, but instead to improve the immune system’s ability to manage it PG 3 1  The first two are local intervention and the last three are systemic intervention Chemoembolization - this is an example of localized chemotherapy as it is delivered to a site locally with a catheter Oncoviruses - this is a localized immunotherapy approach, for example, the use of BCG in the bladder Examples Pancreas: surgery (pancreasectomy) Breast cancer, ER+/HER+ - all 5 pillars: surgery - quadrantectomy + sentinel LN breast RT chemo target - hormone therapy immune - trastuzumab Goals of therapy: Complete eradication of disease cure debulking (before systemic therapy) reconstructive (plastic or mechanic) Palliative care to prolong life expectancy to control symptoms and improve QoL PG 3 2  💡 Palliative care is not end of life care! it is life extension and symptom prevention Preventative therapy to decrease the risk of tumor onset and development (e.g. prophylactic mastectomy and ovariectomy) Surgical palliation pleural, pericardial, peritoneal effusions stabilization of cancer-weakened bones (we won’t let people die with fractures) control of hemorhages surgical bypass of GI, biliary, urinary tract obstruction correction of strictures and adhesions Systemic therapies can be given as neoadjuvant therapy to reduce tumor size before surgery or as adjuvant therapy to eliminate and remaining cancer cells after therapy. Adjuvant therapy is aimed at preventing metastases that may not yet be detectable, but are assumed to exist based on the tumors biology. In summary: for localized diseases → the intent is cure for metastatic or advanced diseases → the intent is extending life expectany and improving its quality PG 3 3  Endpoints in oncology serve as critical measures to evaluate the effectiveness of therapy and determine areas for improvement. tumor response is a primary measure, as reducing the tumor size alleviates symptoms, prolongs life expectancy, and enhances QoL. Progression-free survival → this reflects the time between an initial response to therapy and disease progression. PG 3 4  Overall survival → this refers to the total time that a patient lives after diagnosis or start of therapy. this graph represents patient outcomes over time, showing a decline as the disease progresses or the patient passes due to various causes. The goal in oncology is to delay this decline and in some cases a plateau appears at the end of the curve, indicating a subset of patients who achieve long-term stabilization or even a potential cure → the plateau suggests the possibility of turning certain cancers into chronic conditions. Note that overall survival is not synonymous with cure, it is just the measure of time that a patient lives. It reflects the culmulative impact of multiple therapies and the patients condition overtime. The variability in patient outcomes underscores the heterogeneity of cancer populations. This variation highlights the need for predictive biomarkers to identify those most likely to benefit from specific treatments and help tailor care for better outcomes. Median survival is the point at which 50% of patients have passed. Principles of chemotherapy Utilized mainly in metastatic tumors generally polychemotherapy lines: PG 3 5  first line second line salvage therapy Possibly high-dose CT + Autologous Stem Cell Transplant Mechanism of action Chemotherapeutic are mainly inducers of apoptosis Following genotoxic damage, cells arrest preferentially in two different steps of the cell cycle (check-points), in G1/S and G2/M If the damage cannot be fixed, apoptosis is triggered (chemotherapy is rendered less effective with p53 mutations because the cells lose their ability to initiate apoptosis) G1 arrest may allow damage repair before DNA replication, while G2 arrest before mitosis Key concepts The probability of de novo resistance in any tumor population will increase with increasing number of cells For maximal effect: Treatment should begin as early as possible Multiple mutually non-cross-resistant drugs should be employed as early as possible. They should: Have activity in the same tumour type Have different mechanisms of activity Have non-overlapping toxicity Drugs should be given as frequently as possible and at the maximum tolerated dose Definitions PG 3 6  Dose Intensity: amount of drug delivered per unit time (mg/m2/wk): Dose Escalation: escalating dose per cycle/administration Dose Density: reducing interval between cycles (usually for younger patients) Norton hypothesis: maximal effects of therapy can be obtained when treatment density is enhanced (minimizing regrowth): Be careful with increased toxicity Results of Combination Chemotherapy More effective than single agent Has led to most of the gains in cure, survival Despite “ideal”, most combination regimens are challenging Toxicities may overlap Full doses not possible PG 3 7  (Concurrent vs Sequential Administration: schedule between different drugs) Chemotherapy has a narrow therapeutic index, thus requires precise management. The goal is to widen the therapeutic index as much as possible. This PG 3 8  can be done by using, for example, growth factors to stimulate the recovery of neutrophils (helps mitigate bone marrow suppression) Pharmacology of anti-tumor chemotherapy Due to the narrowest therapeutic index of all drugs is essential to know the 2 factors that affect the efficacy and toxicity of drugs: Pharmacokinetics, i.e. the relationship between plasma drug concentration and time. Is the study of how drugs reach their site of action and are removed from the body (absorption, tissue distribution, metabolism and elimination) –“what the body does to a drug” Pharmacodynamics, i.e. the relationship between the plasma concentration of the drug (or dose, as a surrogate) and its effect. is the study of the biochemical and physiologic effects of drugs and of their mechanisms of action –“what a drug does to the body” The oncologist often applies principles of pharmacokinetics and pharmacodynamics in prescribing chemotherapy. The most common examples are: Dose reduction according to renal or hepatic function Dose reduction as a function of bone marrow reserve (pretreated patients) Use of antidotes as a function of the plasma level of drugs (e.g. leucovorin after MTX) Use of biochemical modulators to increase the antitumor cytotoxicity of a drug (e.g. leucovorin with 5-fluorouracil) Therapeutic index modifiers (e.g. administration of granulocyte growth factors, G-CSF or GM-CSF) PG 3 9  Pharmacokinetics The key parameter of pharmacokinetics is drug clearance Clearance. It is a measure of how quickly a drug is eliminated. The clinician must know the main factors that affect clearance. At a minimum it is necessary to bear in mind: The route of elimination of the drug. If altered, the dose should be reduced (renal failure and platinum; liver failure and anthracyclines). It is essential to correct the dose in cases of simultaneous or close administration of toxic drugs on the same organ (e.g. platinum and aminoglycosides) The body surface. The anticancer drugs should be administered on the basis of body weight or better on body surface area (in m2).- the non- specific distribution highlights the importance of careful dosing to achieve therapeutic levels in the tumor without causing excessive systemic damage. Pharmacodynamics The aim of pharmacodynamics is to study the effect of the drug on the body (generally toxicity as a surrogate pharmacodynamic end-point of activity). The most frequently used pharmacodynamic parameter (pharmacodynamic end-point) is the nadir of WBCs in the blood, in relation to drug concentration. The use of other pharmacodynamic endpoints (eg: non-hematological toxicity rather than hematological, or antitumor response rather than toxicity) generates complex problems that are still unsolved. Toxic effects Related mechanistically to antitumour effect in normal tissues e.g. Myelosuppression (marrow) Mucositis PG 3 10  Hair loss Unrelated to mechanism of antitumour effect e.g. Cardiac effects of anthracyclines Nausea (chemoreceptor trigger zone) Second Malignancies- chemotherapy increases the risk of secondary malignancies, making ongoing preventive screenings essential for cancer survivors Clinical trials These are divided into 4 phases each with distinct objectives designed to ensure safety, efficacy, and applicability in real-world scenarios. Definitions: Dose Limiting Toxicity (DLT) Toxic effects so severe or irreversible such that higher doses are not safe (e.g.: grade 4 ANC for 7 days) Maximum tolerated Dose (MTD) Dose at which DLT is seen in a specified proportion of patients (e.g. 2/3 or 2-3/6) Recommended phase II dose One dose level below MTD Phase 1 Objectives Evaluate different doses of drug(s) in mixed patient population PG 3 11  Primary Define recommended dose Secondary Describe toxic effects Obtain information on clinical pharmacology Document evidence of anti-tumour effects Traditional design Define patient population Select starting dose Define endpoint: dose limiting toxic (DLT) effects Escalate (often in cohorts of 3 pts) Stop escalation at MTD Next lower dose level: recommended phase II dose Assumptions and principles Assumption #1 → major determinant of toxicity is dose Assumption #2 → highest safe dose is "optimal" Assumption #3 → precise estimates of dose effects can be made with small numbers of patients Principle #1 → patients will not be placed at undue risk (this will not be tested on healthy individuals) Assumptions 1 and 2 are no longer applicable to modern targeted therapies. This is because these therapies are designed to act on specific molecular targets, often with little to no toxicity at higher doses. As a result, for targeted therapies, PG 3 12  the optimal dose is determined using surrogate markers like the percentage of drug binding to its target. Once a near-complete binding is achieved (e.g., 98%), increasing the dose further offers no additional benefit. In these cases, toxicity no longer serves as the defining factor for dose determination. Phase 2 Phase 2 trials are designed to evaluate safety and detect early signs of efficacy. The goal here is to establish a potential clinical benefit compared to historical data. Objectives Fixed dose in patient population with specific tumour type Primary Estimate treatment effects (ACTIVITY) using surrogate (of clinical benefit) endpoint(s) and standardized criteria for single agent e.g: Overall response rate (ORR) Progression free-survival (PFS) Determine feasibility and tolerability of combination therapy prior to embarking on phase III trial Determine if a new combination regimen is promising enough to warrant a phase III study Secondary Describe toxic effects Estimate feasibility of treatment delivery Obtain additional information on pharmacology Phase 3 PG 3 13  Phase 3 trials involve large-scale testing to compare the experimental drug directly with the current standard of care. Objectives Primary To detect a difference between two treatments using a clinically meaningful outcome measure (EFFICACY) i.e. survival, quality of life, symptom control Secondary Toxicity, response rate, correlative studies etc Design Seeks to define treatment standards with comparative efficacy studies Uses randomization to minimize imbalance in unknown biasing factors when comparing two or more treatments this may be a double-blind approach to reduce bias in interpreting outcomes. however, this is impratical in some situations, for example, when the administration of the drugs are different. This also has ethical concerns as physicians unaware of the treatment might unintentionally undereact to adverse events Applicability to general practice is important thus multi-centre participation is optimal Economic considerations significantly influence clinical trials. When a drug's improvement over existing treatments is minimal, the financial burden of large trials becomes difficult to justify. PG 3 14