Cancer

13 Oct 2020

Cancer is the condition of uncontrolled cell reproduction. It is a leading cause of death as the longer someone lives, the greater their chance of developing cancer will be; one in two people will develop cancer during their lifetime. The developments of antisepsis and anaesthesia allowed for the treatment of cancer to begin, and from the mid-1800s the ability to treat cancer has been subject to rapid evolution. This has changed the narrative of cancer treatment from one of palliation to that of cure.

Cancerous cells have a number of differences from non-malignant cells which gives rise to their uncontrolled proliferation. Cancer cells have six features which distinguish them from normal cells:

• Sustained growth signals: typically pathway actions will drive the growth of a cell but in a cancerous cell these become autonomous
• Inhibited growth supression: Signals that prevent unrestrained growth are inhibited
• Cell death supressed: the processes that normally govern apoptosis are suppressed so cancerous cells do not respond to external signals that mediate cell death
• Delimited cell growth: the growth potential of the cell is delimited and so cells become immortal with limitless replicative potential
• Neovascularisation: angiogenesis is promoted by cancer cells through downregulation of inhibitory pathways, this also results in neovascularisation which gives an increased supply of blood to tumours
• Metastasis occurs when cancer cells migrate to other areas of the body

Cancer therapy can be thought of as a term encompassing the surgical, radiotherapeutical and medicinal interventions to halt the progression of cancer, and to aim for remission. Combination therapy involves the use of two or more medicines to treat cancer. Using multiple drugs allows for synergistic effects between different chemotherapeutic agents. A drug that may only inhibit the progression of cancer on its own can prove to be curative if given with other agents. This is due to factors like the targeting of different malignant pathways or the initiation of programmed cell death.

Combination therapy also allows for the management of drug toxicities. By using lower doses of a range of drugs less severe side effects from those drugs will be present. Combination therapy is effective for a range of cancers and they are often referred to by acronyms. Some examples of this include: CHOP, CVP, VAMP, FOLFOX, POMP.

There is a number of criteria for the selection of anti-cancer drugs in the treatment of cancer. Cost and effectiveness strongly determine which drugs are used in the treatment of cancer. The National Institute for Health and Care Excellence (NICE) creates guidelines for use by the NHS. They determine the efficacy of a drug in the treatment of a particular condition by reviewing literature and analysing the degree of improvement to patient outcomes balanced against the cost of the drug.

As the resources of a free universal healthcare system, such as the NHS, are finite difficult decisions must be made to produce the most effective benefit for the most people. Assessments are made on an intervention’s ability to add quality years of life to a patient. This is a better evaluation of the efficacy of a given treatment than just assessing the quantity of time added as a patient can experience poor states of health which some would argue are worse than death. Discussions on medical ethics must guide the evaluation of any medical treatment.

When these principles are not followed it can lead to unsustainable expenditure on treatments which are not clinically beneficial. Controversy surrounds the Cancer Drugs Fund which is source of funding for cancer drugs that consultants can apply for. It has been criticised for undermining NICE and costing tax payer’s money - with little benefit to patients, and without extending lives.

Chemotherapy can be non-specific or specific to cancerous cells. Non-specific chemotherapy can exploit the rapid division and replication of cancerous cells. Different drugs work on different parts of the cell cycle.

Condition	Example regimen	Drug classes
Non-Hodgkin lymphoma A cancer affecting the lymphatic system of the body. It can begin in any part of the system. Symptoms can include: painless swellings in the neck, armpit and groin, heavy sweating at night, fever with unknown origin, weight loss and itchiness	RCHOP Rituximab, Cyclophosphamide, Doxorubicin, Vincristine & Prednisolone	Monoclonal antibody, Alkylating agent, Anthracycline antibiotic, Vinca-alkaloid & Corticosteroid
Testicular cancer This is a cancer that affects the reproductive system of men. It most commonly affects young men. Symptoms can include: a lump in the testicle, a heavy scrotum and discomfort or pain in a testicle or the scrotum.	BEP Bleomycin, Etoposide & Cisplatin	Glycopeptide antibiotic, Podophyllotoxin & Alkylator-like agent
Relapsed or refractory Hodgkin lymphoma This is a cancer that begins in the white blood cells. If it is relapsed or refractory that means that it has returned after treatment or has not responded to treatment. Symptoms can include: painless swellings in the neck, armpit and groin, heavy sweating at night, fever with unknown origin, weight loss and itchiness.	BRESHAP Brentuximab, Etoposide, Methylprednisolone, Cytarabine & Cisplatin	Monoclonal antibody, Podophyllotoxin, Corticosteroid, Antimetabolite & Alkylator-like agent

Doxorubicin is a broad spectrum antitumour antibiotic. It belongs to the classification of anthracycline antibiotics and it was discovered as a result of the efforts to synthesise an analogue to daunorubicin. It achieves its cytotoxic effect by binding to DNA in the nucleus of cells and preventing the mitotic process. It is not specific for a phase in the cell cycle.

Vincristine is a vinca alkaloid. Vinca alkaloids were extracted from the pink periwinkle plant. Vinca alkaloids have important cytotoxic effects. They act in the M phase of the cell cycle. They induce cytotoxicity by disrupting the function of microtubules. These structures separate chromosomes during the metaphase and interrupting this process stops these cells from dividing and leads to cell death.

Cytarabine is a nucleoside analogue of deoxycytidine. It is a competitive inhibitor of the enzymes that normally metabolise deoxycytidine. Due to this it inhibits the synthesis of nuclear DNA and therefore acts in the synthesis phase of the cell cycle.

Common side effects of these chemotherapy agents include: Alopecia, anaemia, decreased appetite, eye inflammation, fever, gastrointestinal discomfort. Higher doses of doxorubicin can cause the severe side effect of cardiomyopathy, leading to congestive heart failure. Vincristine has a side effect of neurotoxicity which can lead to sensory and motor neuropathy. Cytarabine can cause severe nausea and vomiting.

Patients that are receiving chemotherapy should be counselled properly to assure adherence to their medication regimen. They should be counselled on side-effects that they may encounter, how to avoid pregnancy whilst they are receiving treatment, what they should do if they develop a fever, any interactions between other medications that they are taking or food they might eat.

Patients that are taking doxorubicin should be advised that it can cause tissue necrosis if extravasation of the drug from the venous system was to occur. They should be advised to call 999 immediately if this occurs.

Patients that are taking vincristine should appreciate the signs of cumulative sensory and motor damage. They can report this to their doctor if this occurs and then dose reduction, treatment interruption or treatment discontinuation can occur if necessary.

Patients that are taking cytarabine should be made aware of the potential for significant gastrointestinal discomfort, nausea and vomiting. They will need to tell their doctor if this happens so that medication to alleviate these symptoms can be considered and dieticians can be consulted if the patient is not able to keep food down.

References

• Mukherjee, S., 2010. The emperor of all maladies: a biography of cancer Simon and Schuster.
• Mokhtari, R.B., Homayouni, T.S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B. and Yeger, H., 2017. Combination therapy in combating cancer. Oncotarget, 8(23), p.38022.
• Folkman, J., 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine, 1(1), pp.27-30.
• Rodriguez, V., Bodey, G.P. and Freireich, E.J., 1973. Combination chemotherapy for lymphomas and leukemias. Disease-a-Month, 19(4), pp.1-40.
• Rosner, F., Hirshaut, Y., Grünwald, H.W. and Dietrich, M., 1975. In vitro combination chemotherapy demonstrating potentiation of vincristine cytotoxicity by prednisolone. Cancer research, 35(3), pp.700-705.
• Speth, P.A.J., Van Hoesel, Q.G.C.M. and Haanen, C., 1988. Clinical pharmacokinetics of doxorubicin. Clinical pharmacokinetics, 15(1), pp.15-31.
• Arcamone, F., 2012. Doxorubicin: anticancer antibiotics. Elsevier.