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Medical oncology

Cancer Therapies - Types And Basic Principles

Apr 1, 2024

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Types Of Cancer Therapies

Basic Principles Of Cancer Therapies

Methods to establish log kill

Radiotherapy

Cancer Therapies - Cytotoxic Therapies

Cancer Therapies - Hormonal Therapies

General Mechanisms Of Resistance

Cancer Therapies - General Mechanisms Of Resistance

Management of Common Side effects of Cancer Therapies

Administering Chemo: The Chemoports

Cytotoxic Therapies: Important And Specific Side Effects

Important ADRS

Summary Of Cytotoxic Therapies

Chemoman Mnemonic

Adverse Effects Of Immune Checkpoint Inhibitors

Adverse Drug Reactions Of Car- T

Cancer Therapies - Types And Basic Principles

Types Of Cancer Therapies

Biologic Therapies	Antitumor Abs: Rituximab and ADCs: Brentuximab-vedotin Rituximab is MAb against CD20 Brentuximab is an Anti-CD30 CD30 is represented by classic HL cells Vedotin is a toxic drug Brentuximab-vedotin, antibody drug conjugates with dual mechanism targets proteins and cancer cells Non-targeted immunomodulator (IMID): BCG, Lenalidomide Intravesical BCG is used for bladder cancer Lenalidomide is an immunomodulator used in MM Bispecific T cell engagers (BiTe): Blinatumomab Brings the T cells to the cancer cell Used in advanced or relapsed stages of ALL Immune checkpoint inhibitors (ICIS): Pembrolizumab Ipilimumab, CTSFO blockers Anti-angiogenic: Bevacizumab Angiogenesis is a hallmark of cancer CAR-T cell therapy: Axicabtagene ciloleucel Adacel, cilta-cel, brexit-cel are the other drugs used Genetically engineered T cells T cell receptors are genetically engineered as per the need, and are taken from the patient Infused in patients targets cancer cells based on the changes. Vaccines/Cytokines: Sipuleucel-T, IFN, IL2 Oncolytic viruses Talimogene laherparepvec Used in certain cases of Melanoma
Cytotoxic therapies	Antimetabolites Anti-microtubule drugs DNA topoisomerase inhibitors Alkylating agents Antitumor antibiotics Asparaginase
Hormonal Agents	Used in hormone responsive cancers like breast, prostate, nutrient cancers
Small molecule pathway inhibitors	Tyrosine kinase inhibitors (TKIs)
Miscellaneous	DNMTi, HDACi DNMTI like Azacitidine, and Decitabine are effective in Myelodysplastic syndrome HDACI like panobinostat, romidepsin; changes the epigenetics

Basic Principles Of Cancer Therapies

Methods to establish log kill

Chemotherapy - Induction is specifically for cancers that are inoperable, such as hematological tumors.. Surgery, if the tumor is operable.

Adjuvant: used following surgery; Neoadjuvant: used prior to surgery in order to reduce the cancer's stage (NACT → Surgery → Adjuvant therapy).

Radiotherapy

Maximum cancer growth is 37% of the initial mass. Clinically detectable cancer is 10⁊ cells (tumor burden logs of cells). Human death is 10¹² (1 kilogram) cells.

Cancer Therapies - Cytotoxic Therapies

Antimetabolites (Specific for S phase)
Class	Drugs	Mechanism
Purine analogs	Cladribine, Fludarabine, Clofarabine, Nelarabine Pentostatin	Metabolites (e.g. CdATP & F-Ara-ATP) → θ RNR & incorporated into DNA & ↓ activity of DNA polymerase (and DNA primase/ ligase) False metabolites incorporated into DNA/RNA
Thiopurine	6-Mercaptopurine 5- Thioguanine
Cytidine analogs	Cytarabine, Gemcitabine	Metabolites (Ara CTP & FdCTP) incorporates into DNA & θ DNA polymerase FdCTP (Gemcitabine) also θ RNA reductase
Pyrimidine analogs	5-FU (IV) Capecitabine (oral)	Metabolized to F-UTP (incorporated into RNA to replace uracil) & FdUMP (θTS)
HMAs	Azacytidine, Decitabine	θ DNMT (incorporates into DNA and RNA)
Folate antagonists	Mtx, Pemetrexed	θ DHFR & TS
Miscellaneous	Hydroxyurea	θ RNR

Nelarabine is a contemporary purine analogue. Using thiopurines causes defective strand growth. Gemcitabine is frequently used, particularly in non-small cell lung cancer Postmenopausal groups utilize aromatase inhibitors for hormonal and endocrine therapy.

Cancer Therapies - Hormonal Therapies

General Mechanisms Of Resistance

Over time, cancer cells either increase the quantity of medicine that leaves the cell and cause resistance, or they limit the amount of drug that enters the cell and cause resistance. Cancer cells can inactivate the drug through an active process, by developing certain enzymes that can inactivate the drug; Or completely alter the drug target; this is common in tyrosine kinase inhibitors;

They have certain critical mutations that can prevent the drug from activating; examples include: generating new mutations in certain key enzymes that activate the drug numerous medications have the potential to harm DNA. Cancer cells have specific mechanisms that speed up the repair of DNA damage, so the repair process is quicker than the damage itself. One cause for developing resistance is the ability of cancer cells to evade death.

Drug resistance is caused by epigenetic changes; for example, methylating TSG inhibits its function; demethylating certain activation genes may cause further cell growth. To put it briefly, mechanisms that lead to resistance Drug target modifications, decreased drug inflow, increased drug efflux, prevented drug activation, DNA damage repair, cell death inhibition, and epigenetic effects

Cancer Therapies - General Mechanisms Of Resistance

Mechanism	Main mechanism	Resistance to drug therapy
Entry	↓ uptake	Antimetabolites (especially Mtx) alkylators (cisplatin, mustards)
Elimination	↑ activity of ABC transporter (MRP1, MDR1 and BCRP)	Taxane, AC, Vinca alkaloids, Epipodophyllotoxins
Alteration or mutation of drug targets	Develop mutations in the EGFR, HER2 or BCR ABL Reduced expression of TS/DHFR	Cetuximab, panitumumab, Trastuzumab & BCR-ABL TKIS 5-FU, Mtx
Drug detoxification and inactivation	GSH conjugation ↑ catabolism	Cisplatin, Doxorubicin 5-FU, Mtx
Impact on apoptosis	Inhibit pro-apoptotic molecules	AC Cisplatin & alkylators Etoposide
DNA replication	↑ DNA repair	AC Cisplatin & alkylators Etoposide

Drug targets that are altered or mutated: MAb, TK inhibitors; • EGFR: Cetuximab is important for SCLC; • HER2: Important for breast cancer; • BCR ABL: Important for CML; • BCR ABL TKIs like
• Dasatinib; Imatinib; Nilotinib; Bosutinib; Ponatinib.

Management of Common Side effects of Cancer Therapies

High risk	Moderate risk	Low risk	Very low/ minimal
Dacarbazine (DTIC) Cisplatin CYC (> 1500 mg/m2)	Carboplatin Cytarabine Ifosfamide Anthracycline CYC (conventional dose)	5 FU Taxanes Etoposide Bortezomib	Bleomycin Busulfan Fludarabine Vinca alkaloids
Dexa + 5HT3 θ + NK1 θ (D1) Dexa + NK1 θ (D2/D3)	Dexa + 5 HT3 θ (Add NK1 θ if receiving CYC + doxo)	5HT3 θ or dexa alone
Other: Antidopaminergics (prochlorperazine, haloperidol), THC & Olanzapine (if refractory)

The most significant side effect caused by chemotherapy is vomiting.
On the first day of triple therapy, NK1-like aprepitant is given in high-risk therapy. Extremely potent dopaminergic antagonists: Prochlorperazine and haloperidol; THC: Tetrahydrocannabinol; Olanzapine, a typical antipsychotic drug; Loperamide, a treatment for diarrhea; Opioid-based medication that acts on the intestine; Octreotide, if not responding;

Treatment for chemotherapy-induced nausea and vomiting. Drugs used in chemotherapy that cause diarrhea – Capecitabine, 5 fluorouracil (5-FU) , S1 chemotherapy to prevent diarrhea caused by 5 fluorouracil, Telafur , Gemeracil, Otteracil , Irinotecan, Tyrosine kinase inhibitors, Chemotherapy-induced mucositis - B: Bleomycin, C: Cytarabine, D: Doxorubicin, F: 5 fluorouracil • Severe: Palifermin, Keratinocyte growth factor. Can stop the development of mucositis.

Alopecia	Maximum risk with Alkylating agents Topoisomerase inhibitors Chemo caps: Reduce the scalp temperature
Gondal dysfunction	Mainly due to Alkylating agents Topoisomerase inhibitors Can consider sperm banking and egg preservation
Pregnancy and cancer	Malignant cancer: Termination is preferred If continuing: Try delaying chemo till 2nd Trimester Contraindication throughout the pregnancy: Antimetabolites
Role of G-CSF	Indications Use if FN risk and 20% H/O FN Neutropenia prior to starting chemotherapy or Active infection while starting chemotherapy Can also be used to harvest stem cells Recurrent infection in neutropenic MDS No evidence of benefit in patients with ongoing FN Start 24-72h after chemo (Not during chemo/Radio-Therapy) Stop if ANC ≥10k

Administering Chemo: The Chemoports

Image 1: Chemoport
Image 2: Present underneath the skin
Image 3: Puncturing
Image 4: X ray image of Chemo port

Cytotoxic Therapies: Important And Specific Side Effects

Toxicity	Common agents & Comments
Cardiotoxicity	Anthracyclines: Produces dose dependent Cardiomyopathy (Echo before starting Rx) High risk if pre-existing CV disease, obesity, smoking, CO-Rx with thoracic RT, other cardiotoxic agents; Female gender Cumulative dose >550 mg/m2 Age <4 or >65 years Trastuzumab: Cardiotoxic agent Causes CMP, Risk is increased when it is combined with anthracyclines. Causes breast cancer 5 fluorouracil: Independently causes coronary spasm Causes vasospastic angina and type 2 MI Dihydropyridine calcium channel blockers(CCB) prevent the coronary spasm Amlodipine Nifedipine Tyrosine kinase inhibitors: Nilotinib Causes prolonged QT, CMP, Angina CYC: Cyclophosphamide Myopericarditis (especially in Bone marrow transplantation) Cisplatin: Usually cause AKI (with decreased Mg/Increased K+; arrhythmia) Produce indirect cardiac effects Bevacizumab: HTN
Pulmonary toxicity	Busulfan Causes Fibrosis or Diffuse alveolar hemorrhage (DAH in ~8% cases) Treatment: High dose steroids Bleomycin: Idiopathic pulmonary fibrosis (~10%). Do Pulmonary Function Tests before starting drugs Treatment: Steroids TKI: especially Dasatinib Pleural effusion CYC Causes pneumonitis, progressive fibrosis Rx: discontinue Bevacizumab Has anti VEGF effect Pulmonary hemorrhage; especially Squamous cell cancer of the lungs(SCC)
Nephrotoxicity or urologic toxicity	Platinum compounds: Cisplatin Causes Proximal convoluted tubule damage Electrolyte abnormalities (Decreased Mg/Increased K) Leads to arrhythmias Pre-treatment with IVF and proper hydration can decrease risk. Methotrexate: Damage by deposition causes crystalluria Treatment IVF IV sodium bicarbonate Cyclophosphamide Hemorrhagic cystitis Due to byproduct acrolein Rx: Mesna Increases the risk for bladder cancer
Neurotoxicity	Platinum Rx(Cisplatin) Glove & stocking neuropathy/Ototoxicity Taxanes: Vincristine (Most important) Sensorimotor long fiber neuropathy Cytarabine: Cerebellar toxicity(Irreversible in 5-10%) Methotrexate cleaving enzyme Late leukoencephalopathy & aseptic meningitis Rx: Intrathecal glucarpidase, Leucovorin Ifosfamide Causes Encephalopathy Rx: Methylene blue & Thiamine
Hepatotoxicity	TKI: Imatinib/Nilotinib Treatment: Discontinue TKIs + Corticosteroids Gemcitabine causes Hepatotoxicity Methotrexate: Can cause Cirrhosis & Portal hypertension Rx: Discontinuation
Dermatological	TKI: Imatinib Causes Dermatitis; Stevens-Johnson syndrome(SJS) Docetaxel, 5-FU, Vinorelbine Serpentine supravenous hyperpigmentation(benign) Bleomycin: Flagellate dermatitis in the back Pyrimidine analogs; Anthracyclines(AC) Hand foot syndrome

Important ADRS

Serpentine supravenous hyperpigmentation

Serpentine supravenous hyperpigmentation

Flagellate hyperpigmentation

Hand foot syndrome

Summary Of Cytotoxic Therapies

Antimetabolites - Cognitive dysfunctions are brought on by intrathecal methotrexate. Antimetabolites also marginally raise the chance of getting subsequent tumors. Patients on corticosteroids have an increased risk of osteoporosis. Vincristine and taxanes can also result in severe neuropathy. Inhibitors of Topoisomerase II. Moderately cardiotoxic o Elevated chance of recurrent cancers. Leukemia acute myeloid syndrome myelodysplastic.

Chemoman Mnemonic

Produces toxicity that is neurogenic Doxorubicin and daunorubicin: cardiotoxic; Cisplatin: nephrotoxic and neurotoxic; Bleomycin: pulmonary toxic. Acute myeloid leukemia; cyclophosphamide: hemorrhagic cystitis of the bladder; alkylating agents: potent bone marrow suppressors.

Adverse Effects Of Immune Checkpoint Inhibitors

CTLA 4: Modifies immunological response- Ipilimumab, a monoclonal antibody that blocks it, is used to treat melanoma. PD1 and PD L1 ligands: These ligands suppress the immune system's attack on cancer cells. PD-1 inhibitors – Pembrolizumab, Nivolumab, Cetrimiplimab, Anti-PDL1/2 blockers – Atezolizumab, Avelumab, Durvalumab.

Target	Drugs	Indications	ADRs
PD-1	Nivolumab Pembrolizumab Cemiplimab Dostarlimab	Melanoma, NSCLC RCC HNSCC HL	Rash > hypothyroid, pneumonitis, colitis, hepatitis/T1DM (PD1) & hypoadrenalism (with PD-L1)
PD-L1	Atezolizumab Avelumab Durvalumab	Urothelial carcinoma NSCLC SCLC HCC
CTLA-4	Ipilimumab	Melanoma RCC Mesothelioma	Rash > Colitis Hypophysitis Hypothyroid Pneumonitis Hepatitis

Rash is the immune checkpoint inhibitor's most frequent side effect.

Adverse Drug Reactions Of Car- T

Chimeric antigen receptor T cell treatment, or CAR-T, causes fever, hypertension, and shock. Cytokine release syndrome, or CRS, is the result. As a result of proliferating T cells' overwhelming release of cytokines; When CAR-T cells are activated, there may be an overabundance of immune-signaling chemicals called cytokines released. Flu-like symptoms and even severe reactions may result from this. An essential component of CAR-T treatment is CRS management.
The immunological effector cell-associated neurotoxicity syndrome (ICANS), causes cerebral edema, defecation; agitation; aphasia; fatigue; ostundation.

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