Principles of medical therapy
Introduction
Medications in cancer care are utilised to achieve the following goals:
- to exert anti-cancer effects by killing or controlling cancer cells
- to treat complications arising from anti-cancer therapies
- to minimise the effects of cancer on body parts
- to control symptoms from cancer and complications of cancer treatments.
Medications to achieve cancer cell death or cancer control
Chemotherapy, small molecules, monoclonal antibodies and hormonal agents are used for this purpose.
Chemotherapy
These agents achieve cancer control by several mechanisms. Some examples include:
- damage to the DNA by various mechanisms during different phases of the cell cycle
- inhibition of mitosis by interfering with microtubules.
Chemotherapy is used for the following purposes:
- cure (e.g. leukaemia, lymphoma, germ cell tumours)
- adjuvant, to eradicate micro metastasis following surgery or radiotherapy (e.g. breast, colon, ovarian cancers)
- in combination with radiotherapy to sensitize radiotherapy (e.g. head and neck, rectum, lung ,cervical cancers)
- palliation of symptoms and prolong survival (e.g. most metastatic cancers).
Small molecules
Many new medications inhibit various kinases along the signal transduction pathways that are associated with cell proliferation, survival, metastasis and angiogenesis.[1] Most of these agents inhibit the activity of these kinases by competing for ATP binding.
| Medication | Target Kinases | Current Use |
|---|---|---|
| Imatinib | Bcr-abl | Chronic myeloid leukaemia, gastrointestinal stromal tumour |
| Erlotinib,gefitinib | EGFR | Non-small cell lung cancer |
| lapatinib | Her1 and 2 receptor | Breast cancer |
| Sunitinib | PDGFR, VEGFR, Kit | Renal, GIST |
| Afinitor | mTOR | Breast, renal |
Monoclonal antibodies
Humanised monoclonal antibodies cause cancer cell death by the following mechanisms:[2]
- direct action of antibody (receptor blockade or agonist activity, delivery of a drug or cytotoxic agent)
- E.g. Trastuzumab in HER2 positive breast cancer
- Complement dependant cytotoxicity
- Antibody-dependent cellular cytotoxicity (ADCC)
- E.g. Rituximab binds to CD 20 on lymphoma cells and stimulate ADCC
- Regulation of T cell function
- E.g. Ipilimumab
- In cancers like melanoma, antigen presenting cells (APC) present tumour antigen to the T cell via MHC complex. When tumour antigen binds with T cell receptors (B7 on APC with B28 on T cells), this leads to T cell activation and release of inflammatory proteins. When intracellular CTLA4 molecule is expressed on the surface of the T cell, binding of CTLA4 to B7 turns off the T cell activation. Ipilimumab binds to the CTLA4 and inhibit the binding of CTLA4 and B7. This means the T cell remains activated. Ongoing release of inflammatory proteins is expected to exert tumour control.
- Specific effect on tumour vasculature and stroma
- E.g. Bevacizumab binds to VEGFR on stromal tissues and inhibit angiogenesis within cancer deposits.
Hormonal agents
These agents inhibit the actions of various hormones on hormone responsive cancer cells. Side effects are usually related to hormone depletion.
| Medication | How it works | Used in |
|---|---|---|
| Tamoxifen | Oestrogen receptor blockade | Breast cancer |
| Aromatase inhibitors | Inhibition of conversion of androgens to oestrogen | Breast cancer |
| Gonadotrophin releasing hormone(GnRH) | Decrease the ovarian production of oestrogen and testicular production of testosterone | Breast cancer and prostate cancer |
| Anti androgens | Androgen receptor blockade | Prostate cancer |
Managing chemotherapy side effects
Most side effects are due to non-specific damage to normal cells. They do not always occur and not all the patients experience the same side effects.[3]
Examples:
- Nausea, vomiting -- Some drugs are more emetogenic than others; prophylactic antiemetic medications use can decrease the incidence. Details are found in the “Medical oncology hand book for junior medical staff”[3] accessed via the following link: http://www.health.qld.gov.au/townsville/Documents/clinicians/med-onc-jnr-handbook.pdf
- Alopecia -- Not all the medications cause alopecia. Most breast cancer medications cause complete alopecia; most colorectal regimens do not cause complete alopecia.
- Myelosuppression and neutropenic sepsis -- Neutropenic sepsis is treated with broad spectrum antibiotics. Risk of neutropenia can be reduced by the use of granulocyte colony stimulating factors. Anaemia and thrombocytopenia can be treated with transfusions of packed red cells and platelets respectively.
- Fatigue
- Infertility -- Not all the drugs cause this side effect. It is important that pregnancy is avoided during and at least 12 months after completing chemotherapy. In ER negative cancers, ovarian suppression during chemotherapy can reduce the risk of infertility.
- Effects on other organs -- E.g. cisplatin and neuropathy, anthracyclines and cardio toxicity, bleomycin and interstitial pneumonitis.
Medications to minimise the impact of cancer on organs
Examples:
Bisphosphonates (e.g. zelodronic acid, pamidronate) or RANKL inhibitor denosumab can decrease the incidence of skeletal related events in patients with bone metastasis from various cancers, including breast, prostate and multiple myeloma. Skeletal-related events include fracture, pain and hypercalcemia. These agents can also decrease the rate of osteoporosis/osteopenia caused by anti-hormonal agents like aromatase inhibitors.
Note: RANK is a surface receptor on pre-osteoclasts. RANK is activated by RANKL (RANK ligand) found on the surface of osteoblasts. Binding of RANK to RANKL leads to maturation of pre-osteoclasts to mature osteoclasts and subsequent destruction of the bones.[4]
Managing symptoms caused by cancer or complications of treatments
When we attempt to treat cancers, it is important to make sure the quality of life of the patients is improved or maintained by controlling the cancer-related symptoms and treatment-related complications. Patients with metastatic disease can gain important benefits when their care is shared between various health professionals, including palliative care professionals.
References
- ↑ Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009 Jan;9(1):28-39 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19104514.
- ↑ Scott A, Wolchok J, Old L. Antibody therapy of cancer. Nature Reviews Cancer 2012 Apr [cited 2014 Jul 22];12:278-287 Available from: http://www.nature.com/nrc/journal/v12/n4/abs/nrc3236.html.
- ↑ 3.0 3.1 Joshi A, Otty Z, Sabesan S, Varma S. Medical oncology hand book for junior medical officers. Townsville: Department of Medical Oncology Townsville Cancer Centre; 2013 [cited 2014 Jul 22] Available from: http://www.health.qld.gov.au/townsville/Documents/clinicians/med-onc-jnr-handbook.pdf.
- ↑ McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006 Feb 23;354(8):821-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16495394.