Principles of Clinical Radiation Oncology and Chemotherapy Notes

Principles of Clinical Radiation Oncology and Chemotherapy

Principles of Clinical Radiation Oncology and Chemotherapy Introduction:

Radiation oncology is that discipline of human medicine concerned with the generation, conservation, and dissemination of knowledge concerning the causes, prevention, and treatment of cancer and other diseases involving special expertise in the therapeutic applications of ionising radiation.

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Leopold Freund was the first to report in 1897, the use of ionising radiation to “cure” a large nevus pigmentosus on the back of a young girl. With time, ionising radiation became more precise; high-energy photons, electrons, protons, neutrons, and carbon ions became available; and treatment planning and delivery became more accurate and reproducible.

 

Advances in computer and electronic technology fostered the development of more sophisticated treatment-planning and delivery techniques, leading to the development and eventually broad implementation of three-dimensional conformal radiation therapy (3DCRT), and intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), et

Radiation

The term radiation applies to the emission and propagation of energy through space and material medium. Radiation travels with the speed of light in a vacuum and interacts with living or nonliving matter resulting in varying degrees of energy transfer to the biological medium. This process of deposition of energy within the cells is brought about by ionisation (removal of an orbital electron) of atoms and molecules. Ionising radiations are off very high frequency (3 × 1021 hertz) and short wavelength (1013 m) electromagnetic waves.

Ionisation can occur within the nuclear DNA molecule of a cell (directly acting) or interaction with other molecules, mainly water (H2O) to produce free radicals (indirectly), which in turn can damage DNA and result in cell death or mutagenesis.

By damaging DNA, radiation interferes with cell division and can result in reproductive death of a cell. This process in a malignant tumour could mean the loss of its ability for uncontrolled cell division or proliferation. This process is unselective; it occurs both in cells of normal tissues and in those of tumours.

Therapeutic usefulness of radiotherapy, therefore, depends on the differential sensitivity of tissues (normal v s tumour cell), on careful treatment planning and dose prescription to minimise normal tissue damage and the patient’s tolerance to radiation.

Dose Fractionation

1. The 5 Rs of radiobiology provide the basis for fractional radiotherapy. In clinical practice dividing a dose into a number of fractions has the following advantages:
2. The acute effects of single doses of radiation can be decreased with fractionation. The patient’s symptomatic tolerance improves with fractional radiation.
3. Fractionation exploits the difference in recovery rate between normal tissues and tumours. Effects on normal tissues are less because of repair of sublethal damage between dose fractions and normal cellular repopulation.
4. Radiation-induced redistribution of cells within the cell cycle tends to sensitise the rapidly proliferating cells, which is seen more in tumours.
5. Radiosensitivity of cells depends markedly on the phase of the cell cycle at which they receive the radiation. Cells in mitosis and G2 phase are the most sensitive and cells in early Gl, and late S phases are the most resistant.
6. Reduction in the number of hypoxic cells is brought about through cell kill and reoxygenation. Also blood vessels compressed by a growing cancer are decompressed as the cancer shrinks, permitting better oxygenation.

Oxygen Effect:

The biologic effects of ionising radiations are greatly influenced by the presence of normal oxygen concentration within the cells. The absence or low oxygen content conveys a resistance to radiation requiring about three times the dose to produce the same biologic effects.

Certain solid tumours and large tumours are likely to contain 10–15% of hypoxic cells.

For routine practice the “Conventional or Standard” dose fractionation schedule is followeThis consists of 180–200 cGy fraction per day, and 5 fractions per week over 4–6 weeks (depending on the total dose). The choice of optimal dose/time/fractionation schedules for various tumours should be individualised according to the cell kinetic characteristics and clinical observations.

Radiocurability refers to the eradication of tumour at the primary or regional site and reflects the direct effect of irradiation, which may or may not parallel the patient’s ultimate outcome.

Probability Of Tumour Control

It is axiomatic in radiation therapy that higher doses of radiation produce better tumour control, and numerous dose–response curves (sigmoid in shape) in a variety of tumours have been publishe

For every increment of dose, a certain fraction of cells will be killeTherefore, the total number of surviving cells will be proportional to the initial number present and the fraction killed with each dose. Thus, it is apparent that various levels of irradiation yield a different probability of tumour control, depending on the extent of lesion or number of clonogenic cells present.

For subclinical disease (103–4 cells) in squamous cell carcinoma of the upper respiratory tract or for adenocarcinoma of the breast, doses of 4500–5000 cGy result in control of disease in over 90% of patients. For microscopic residual disease or cell aggregates greater than 106/109 are required for the pathologist to detect them. Therefore, these volumes must receive higher doses of radiation in the range of 6000–6500 cGy in 6–7 weeks for epithelial tumours.

For clinically palpable tumours (gross disease), doses of 6000 cGy (for T1) to 7500 cGy to 8000 cGy (for

T4 tumours) are required (200 cGy/day/5 fractions weekly). This dose range and probability of tumour control have been documented for various tumours.

Radiotherapy—Sources And Methods Of Delivery

Radiotherapy is the therapeutic use of high-energy ionising radiation in the treatment/management of malignant disease.

These are either electromagnetic waves, X-rays, gamma rays or corpuscular (subatomic particles) electrons, protons, neutrons, alpha particles, or heavy ion nuclei. Ionising radiation penetrates tissues to different depths according to its type of energy and physical nature. Radiotherapy treatment planning is an important part of the radiation oncologist’s work.

Source Of Radiation

Gamma and beta rays from radioactive isotopes (cobalt 60, caesium 137, indium 197) and X-rays and electrons from a high energy X-ray machine (linear accelerator). Protons, neutrons and heavy ion nuclei from cyclotrons. X-rays and gamma rays are identical in properties but are produced by different sources. Ionising radiations can be classified according to their density of ionisations per unit length of the distance in the absorbing media as low and high LET (linear energy transfer) radiation.

Ionizing Radiation

• Low LET—X-rays, gamma rays and electron.
• High LET—neutrons, protons, α-particles and negative ions.
• High LET radiation has a mass heavier than electrons.
• Hence, they cause dense ionisation and are biologically more effective (damaging) than low LET radiation. They are also less dependent on repair of sublethal damage, cell cycle phases and oxygen content of the cells for radio-sensitivity.
• High LET radiation is available in limited cancer centres around the world, require expensive equipment to produce and are undergoing clinical trials.

Methods Of Delivery

Ionizing radiation may be delivered clinically in three ways:

1. External Beam Irradiation:

From sources at a distance (usually 80–100 cm) from the body surface. This includes 60Co Teletherapy Units and X-ray sources, such as linear accelerators

Advantages of Megavoltage Beam RT:

1. Deeper penetration
2. Sharp beam edges
3. Skin sparing
4. Equal absorption in bone and soft tissues
5. Improved dose distribution within tissue.

2. Brachytherapy:

Brachytherapy refers to use of radiation sources in or close to the tumour.

Use of sealed (closed containers) radioactive sources for radiation treatment from a short distance.

Types of Brachytherapy:

1. Intracavitary (within a cavity), e.g. uterine cavity, vaginal cavity, oesophageal and bronchial lumen.
2. Interstitial is when radioactive needles and wires are inserted into and around a tumour.
3. Surface moulds or plaques as radioactive surface applicators, e.g. skin cancer, eye cancers. With this mode of therapy a high dose can be delivered locally to the tumour with rapid dose fall off in the surrounding normal tissue. In the past, brachytherapy was carried out mostly with radium or radon sources. Currently, use of artificially produced radionuclides such as 137Cs (caesium 137), 192Ir (iridium 192), 198Au (gold 198), and 125I (iodine 125) is rapidly increasing.

New technical developments have stimulated increased interest in brachytherapy.

Source Of Radiation Examples:

1. Introduction of improved artificial isotopes
2. Manual afterloading devices to reduce personnel exposure
3. Remote afterloading, high dose rate (HDR) machines, have increased accuracy, improved dosimetry, reduced (short) treatment time, treatment on outpatient basis and have improved patient compliance.

Brachytherapy is used very often. Combined with external beam treatment and rarely alone (early stage). The rationale behind combining the two is to treat the primary site and regional spread (very often subclinical disease) with external RT and to deliver a higher dose (boost) to the primary (gross disease) with brachytherapy. Aim is not to exceed the normal tissue tolerance and at the same time the tumour should receive adequate curative dose. Brachytherapy can also be used as palliative therapy, e.g. bronchial and oesophageal obstruction.

3. Internal or Systemic Irradiation:

From unsealed radioactive sources (i.e. ¹³¹I, ³²P, ⁸⁹Sr) administered enterally, intracavitarily or intravenously, for diagnostic (nuclear medicine) and therapeutic purposes, e.g. carcinoma thyroid, bone tumours and thyrotoxicosis.

Measurement Of Ionising Radiation

1. The Roentgen is a unit of exposure. It is a measure of ionisations produced per unit volume of air by X-rays and gamma rays and cannot be used for photon energies above 3 Mev.

• The SI unit for exposure is Coulomb per kilogram (C/kg).
• 1 R = 2.58 × 10⁴ C/kg air.

2. Radiation absorbed dose (RAD):

• Absorbed dose is a measure of the biologically significant effects produced by ionising radiation. Absorbed dose = De/dm, De is the mean energy imparted by the ionising radiation to material of mass dm. The old unit of dose is rad and represents the absorption of 100 ergs of energy per gram of absorbing material.
• 1 rad == 100 ergs/g = 102 J/kg
• The SI unit of absorbed dose is gray (Gy) and is defined as:

1 Gy = 1 J/kg

Thus the relationship between rad and gray is 1 Gy

= 100 rad or 1 cGy = 1 rad.

Electron Beam Therapy

Source Of Radiation Source:

Mainly linear accelerators.

Energy:

The most useful range for clinical use is 6 to 20 Mev.

Source Of Radiation Use:

1. Superficial tumours up to a depth of 5 cm
2. Local boost

Source Of Radiation Advantages:

1. Characteristic sharp dose fall off beyond the tumour
2. Dose uniformity within the target volume

Principal Applications:

1. Treatment of skin and lip cancers
2. Chest wall irradiation for breast cancer
3. Boost dose to nodes and tumour bed
4. Head and neck cancers.

Clinical Use of Radiotherapy:

Like surgery and chemotherapy, radiation therapy (RT) has definite indications and contraindications for its application.

It can be used alone to cure or, in combination with other methods, as an adjuvant. Currently, 50–60% of all patients with cancer receive RT during the course of their illness. If properly used, 50% of these patients could get a cureFor the other half, incurable by any current method, palliation of specific symptoms and signs can improve quality of life.

Differences between radical and palliative radiotherapy:

Before treating a patient with radiotherapy, the radiotherapist must be satisfied that the working diagnosis is correct, pretreatment investigations and staging have to be complete. Then the radiation oncologist must address two questions:

1. Is the treatment intent curative or palliative?
2. What is the best approach to achieve this goal?

The first question is vital, for there are important differences between radical and palliative radiotherapy. The second question recognises that cancer can be treated by surgery, radiotherapy and drugs. In many instances, radiotherapy is the best approach. In view of the increasing complexity of curative cancer management for many tumours, with different combinations of surgery, radiotherapy and chemotherapy for different stages of the disease, require a co-ordinated multidisciplinary approach. The correct initial choice gives the best prospect for cure or good palliation.

As A Primary Curative Modality

1. RT frequently may be the sole agent used with curative intent for anatomically limited tumours of the retina, optic nerve, brain (craniopharyngioma, medulloblastoma, ependymoma), spinal cord (lowgrade glioma), skin, oral cavity, pharynx, larynx, oesophagus, uterine cervix, vagina, prostate and reticuloendothelial system (Hodgkin’s disease, stages 1, 2 and 3A).
2. When no other potentially curative treatment exists. Some cancers remain localised for all or much of their natural history. These cancers might also be unresectable by virtue of their anatomical location or because of local infiltration into surrounding normal/ vital structures, which would mean that surgery will severely affect physiological function, e.g. locally advanced head and neck cancer, cervical cancers stage 2b-3, medulloblastoma (alternative to surgery for inaccessible and inoperable malignancies).
3. Where alternative therapy is considered more “toxic”. Carcinoma of the larynx, anal canal, breast can all be managed by ablative surgery and in each case the anatomy and physiology of the respective organ is lost. Each of these cancers can be managed by irradiation with preservation of anatomy and function. Preservation of organ and its function (larynx, breast, anal canal, limbs, cervix, tongue, bladder).

Adjuvant For Curative Therapy (Combined Modality)

RT is combined with surgery for advanced cancers of the head and neck, cancers of the lung, uterus, breast, urinary bladder, testis (seminoma), rectum, soft tissue sarcomas and primary bone tumours.

RT is an adjuvant to chemotherapy for some patients with lymphomas, lung cancers and cancer in children (rhabdomyosarcoma, Wilms’ tumour, neuroblastoma). In some clinical situations the combined benefits of surgery, RT and chemotherapy might be exploiteIt has been most useful in the management of breast cancer, bone sarcoma and Wilms’ tumour.

Combined Treatment (Surgery And Radiation Therapy)

In many situations radiation therapy alone is inadequate for achieving maximum cure levels. This can be because the number of tumour stem cells is too large, some or all of the cancer cells are radioresistant, or tolerance of the contiguous normal tissues is too low. The rationale for combining surgery and radiation therapy is the differing mechanisms of the two disciplines. Radiation therapy fails at the centre of the tumour where the concentrations of the tumour cells is the largest and the conditions may be hypoxic (less sensitive to RT).

Surgical resection fails because the tumour extends further than the margins of excision, infesting contiguous tissues with undetectable microscopic foci. Radiation therapy is efficient in the sterilisation of these tumour cell numbers that are well vascularised, and the surgical resection is efficient in removing the gross necrotic tumour masses. Radiation can be combined with surgery either preoperatively or postoperatively.

Aims and Advantages of Preoperative RT

1. Unresectable cancer to resectable cancer
2. Prevent iatrogenic metastases
3. Reduction of size and vascularity
4. Destroys microscopic foci beyond surgical margin

Source Of Radiation Disadvantages:

1. Delay in surgical (primary) treatment
2. Delay in wound healing
3. Pathologic downstaging to influence other adjuvant treatment
4. Alters anatomical staging (precise pathological extent)
5. Inability to tailor RT to high risk areas.

Postoperative RT

Clinical situations may indicate different sequences but such combinations of surgery and radiation therapy improve the local tumour control rate for many advanced cancers. Combined therapy may also improve the cure rate, at the same time reducing the morbidity associated with more aggressive single modality treatment.

Combination Of Radiotherapy With Chemotherapy

In general, chemotherapy is used in an adjuvant way to control subclinical disease elsewhere in the body or in an additive way to enhance the local effects of the radiation to achieve higher rate of local control. Many other agents will act in both ways. Agents of choice are those whose toxic effects are in organs not included in the radiation target volume. An example is the combination of the cisplatin compounds with radiation therapy for head and neck cancers. Here, the toxicity of chemotherapy is primarily haematogenous and renal. The toxicity of RT is on the oral mucosa.

Chemotherapy could be combined with RT in three main ways:

1. Neoadjuvant: 1–3 courses before definitive RT.
2. Adjuvant: After completion of definitive RT.
3. Concurrent: During a course of radiotherapy.
4. Combinations of the above.

Prophylactic Cranial Radiation

Certain cancers have a high incidence of developing brain (CNS) metastases even after their primary disease is controlled, because of the blood–brain barrier which can act as a sanctuary site for relapse. Among such patients, it is possible to reduce their local CNS relapse rate and improve survival by treating the CNS by prophylactic cranial RT ± intrathecal chemotherapy. The total dose needed is low (18–24 Gy) and has minimal side effects, e.g. acute lymphoblastic leukaemia/high grade lymphomas.

Management Radiotherapy Reactions

• The incidence of systemic symptoms from radiotherapy is variable. In broad terms, the larger the treatment yield, the fraction size and the total given dose, the greater will be the chance of the patient developing problems. The dose of radiation that can be delivered is limited by acute reactions and by late irreversible organ/tissue damage. Each organ has a known tolerance which should not be exceeded.
• However, in order to achieve a given level of tumour control probability certain amount of normal tissue sequelae are unavoidable.
• During a course of radiotherapy mild to moderate grade acute reactions occur frequently and can be usually conservatively managed and might require a short break in the treatment, whereas chronic reactions are usually the dose limiting complications. Severe grade reactions should be avoided using proper time dose fractionation regimens, accurate treatment planning and execution.
• Some of the important acute reactions following RT, their threshold doses and management

Complications and management of RT:

Advances In Radiation Therapy

Current research in radiation oncology is of such significance that it promises a new standard of care for patients with cancer. Recent advances in radiation therapy include efforts to improve the effectiveness of radiation and to improve the quality of life of treated patients. Innovations in radiobiology, imaging technology, computer technology and treatment machine technology has resulted in marked changes in the way radiotherapy is practised at present. The newer methods aim at increasing the accuracy of treatment, planning and dose delivery using the highly sophisticated features offered by the modern day equipment.

1. 3-D conformal radiotherapy (three-dimensional treatment planning and conformal dose delivery). In 3-D CRT, patient immobilisation, image-guided treatment planning and computer-controlled treatment delivery can create a radiation dose distribution that conforms to the shape of the tumour volume. The tumour volume containing the cancer and areas of potential cancer is much more accurately outlined as are normal tissues to be avoideThe target radiation dose can be increased when necessary without increased toxicity to normal tissue. This is accomplished using volumetric CT data in a 3-D treatment planning computer.

2. IMRT: IMRT is an advanced form of 3-DCRT. It is one of the technologically most advanced treatment methods available in external beam radiation therapy. IMRT allows very precise external beam radiotherapy treatments. Rather than having a single large radiation beam pass through the body, with IMRT, the radiation is effectively broken up into thousands of tiny pencilthin radiation beams of varying intensity with millimetre accuracy. These beams enter the body from many angles and intersect on the cancer. This results in a high dosage to the tumor and a lower dose to the surrounding healthy tissues.

• Intensity modulation radiotherapy can allow us to treat tumours to a higher dose, retreat cancers that have previously been irradiated, and safely treat tumours that are located very close to delicate organs like the eye, spinal cord, or rectum. Simply put, this can translate into a higher cancer control rate and a lower rate of side effects.

3. SRS/SRT (stereotactic radiosurgery and radiotherapy): High-dose highly focused radiation therapy for small (SRS = Single fraction, SRT = Multiple fractions) target lesions (<2–4 cm) can be accomplished by either gamma knife (multiple, fixed, precisely aimed cobalt teletherapy beams) or stereotactic radiation therapy (multiple rotational arcs of photon beams from a linear accelerator). Both techniques are similar in their use of standard energy photon beams for treatment and rely on meticulous patient immobilisation to deliver treatment to a precisely localised target within a co-ordinate mapping system. These techniques have been widely used and well described for the treatment of intracranial neoplasms (meningiomas, acoustic neuromas and metastatic tumours) and for the ablation of arteriovenous malformations and ocular melanomas. [Equipment used: 1. Gamma knife (Multiple 60Co sources) or 2. X- knife (modified linear accelerator)].

4. IGRT:

• Image-guided radiation therapy (IGRT), is one of the most cutting-edge innovations in cancer technology available. Tumors can move, because of breathing and other movement in the body. Realtime imaging of the treatment target and normal organs during each treatment allows for minimisation of reduction of irradiated volumes, as well decreases the chance of missing a target, helping to limit radiation exposure to healthy tissue and reduce common radiation side effects.
• In IGRT, the linear accelerators are equipped with imaging technology that take pictures of the tumour immediately before or even during the time radiation is delivered. There are numerous types of imaging modalities that can be incorporated into an IGRT system.

Examples include Ultrasound images, low-energy (kV) CT scan images, high-energy (MV) CT scan images, etc.

5. SBRT: Stereotactic body radiation therapy (SBRT) is a technique that utilises precisely targeted radiation to a tumour while minimising radiation to adjacent normal tissue. This targeting allows treatment of small or moderate sized tumours in either a single or limited number of dose fractions. SBRT has been used in hepatocellular carcinoma, lung cancer, prostate cancer, pancreatic cancer. As with any form of radiation therapy, careful attention to matters of patient selection and technical quality assurance is essential for the effective and safe implementation of SBRT.

6. Proton therapy:

• Proton beam: Proton radiation reduces the dose to normal tissues by allowing for more precise dose delivery because of the unique physical properties of heavy particles. Protons penetrate tissue to a variable depth, depending upon their energy, and then deposit that energy in the tissue in a sharp peak, known as a Bragg peak. This rapid dose fall off at a depth that can be controlled by the initial energy of the protons allows for decreased radiation to adjoining normal tissue by a factor of 2 to 3.
• Protons are used for uveal melanoma (ocular tumours), skull base and paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas, pediatric neoplasms (such as medulloblastoma) and prostate cancer.

7. Intravascular brachytherapy: Arterial renarrowing after angioplasty or restenosis occurs in 30 to 40% of patients and results from neointimal proliferation and constrictive remodelling of the angio-injured artery. Coronary stenting has led to a 30 to 50% decrease in the rate of restenosis primarily by preventing the constrictive remodeling of the artery but at the cost of an increase in neointimal proliferation. The system used for intra-arterial beta-radiation therapy has Yttrium-90 beta ray emitting source (half-life, 64 hours; maximal energy, 2.284 MeV), a centering balloon and an automated delivery device. An 18-Gy dose not only prevents the renarrowing of the lumen typically observed after successful balloon angioplasty but actually induces luminal enlargement.

Drawback (all techniques):

• High cost of treatment (expensive equipment + time and labour-intensive)
• Lack of long-term data (survival/late morbidity).

8. CyberKnife: CyberKnife radiosurgery is the noninvasive alternative to surgery for the precise treatment and effective removal of cancerous tumours from the body.

• The system has a miniaturized linear accelerator mounted on a robotic arm with 6 different points of axis where it can bend, turn, tilt or swivel with submillimetre accuracy.
• Destroys tumours with highly precise beams of radiation, tumours virtually anywhere in the body, quickly, painlessly and without downtime or hospital stay in one to five sessions (hypofractionation).
• Thus offers new hope to patients who have inoperable or surgically complex tumours and for those who may be looking for an alternative to more invasive surgery.

Oncology Concise Concepts Of Chemotherapy

Introduction

Cancer (also called malignancy) is a term used for diseases in which abnormal cells divide without control and can invade and spread to nearby and distant tissues and organs through the blood and lymph systems. There are different types of cancers depending on the tissue of origin. Carcinoma is a cancer that develops in the skin, mucosa, or in tissues that line or cover internal organs. Sarcoma is a cancer that originates in the bone, cartilage, or other connective or supportive tissue.

Leukemia is a cancer of the blood and bone marrow. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system like lymph nodes, spleen or bone marrow.

Oncology is a branch of medicine that specializes in the diagnosis and treatment of cancer. It includes:

• Medical oncology—the branch that deals with the use of chemotherapy or drugs to treat cancer.
• Radiation oncology—the branch that deals with use of radiation therapy to treat cancer.
• Surgical oncology—the branch that deals with use of surgery to treat cancer.

Epidemiology of Cancer:

The new global cancer data suggests that the global cancer burden has risen to 18.1 million cases and 9.6 million cancer deaths. The International Agency for Research on Cancer (IARC) estimates that one in five men and one in six women worldwide will develop cancer over the course of their lifetime, and that one in eight men and one in eleven women will die from their disease. A number of factors appear to be driving this increase, particularly a growing and ageing global population and an increase in exposure to cancer risk factors linked to social and economic development. For rapidly growing economies, the data suggests a shift from poverty or infection related cancers to those associated with lifestyles more typical in industrialized countries.

According to GLOBOCAN 2018 data, in 2018 there were 11,57,294 new cancer cases in India in both men and women, 7,84,821 deaths and 22,58,208 people living with cancer (within 5 years of diagnosis). The top 5 cancers that affect Indian population are breast, oral, cervical, gastric and lung cancers.

Cancer Biology:

Most cancers arise as a result of multiple somatic mutations to DNA and occur only after a cell has acquired many mutations to create chromosomal instability. As a cell acquires mutations, it undergoes a variety of changes. There is a continuum from a perfectly normal cell to a cancer cell. Along this continuum, cells often change their appearance and behaviour, a phenomenon known as dysplasia, before they become malignant. While mutations in DNA are a fundamental cause of cancer, other causes exist as well. Epigenetic changes affect both DNA and associated chromatin, without affecting the nucleotide sequence, and contribute to carcinogenesis by influencing gene expression.

Genes:

1. Oncogenes: Proto-oncogenes are essential to growth and mitosis in a normal cell. However, mutations in proto-oncogenes give rise to oncogenes, which contribute to the formation of cancer cells.
2. Tumour suppressor genes: Tumour suppressor genes represent another common class of genes frequently altered in cancers. Tumour suppressor genes encode proteins which downregulate cell proliferation and control cell cycle checkpoints necessary for cell growth. Tumour cells commonly exhibit mutations in tumour suppressor genes such as Rb and p53.
3. DNA repair genes: DNA mutations can occur with remarkable frequency in the life of a cell through errors introduced during replication. A variety of DNA repair enzymes exist to remove and fix these mutations. Loss of DNA repair enzymes leads to an increased risk of permanent DNA damage with consequences including progression to cancer.

It is thought that cancers possess a population of stem cells sufficient to propagate a tumour. These cancer stem cells need not arise from a pool of normal stem cells. Rather, somatic mutations may result in a differentiated cell reverting to a stem cell phenotype. If this hypothesis is correct, true eradication of cancers would require therapy targeting the stem cell population. Cancer cells are prone to acquire additional mutations. It is therefore common for cancers to have multiple sub-clones of the original malignant cell.

These new clones possess different metastatic abilities or develop resistance to different chemotherapeutic drugs. The presence of clonal variation within cancers explains the frequently observed phenomenon of cancers initially shrinking in response to chemotherapy, but subsequently growing back.

Metastases are the hallmark of a malignant tumour. They represent spread of tumour cells away from the primary tumour. Normal cells typically adhere to their neighboring cells and the surrounding extracellular matrix. A variety of protein families, including integrins, cadhedrins, selectins, and other cell adhesion molecules (CAMs) anchor cells to one another. Mutations in CAMs are frequently present in cancer cells.

These mutations make it easier for cancer cells to disaggregate from one another in order to spread out beyond the normal cell’s usual anatomic boundary. In order to metastasize, a cell or group of cells must detach from the primary tumour, digest and move through the intercellular matrix and penetrate the vascular basement membrane.

Enzymes, like matrix metalloproteinases, are upregulated in cancer cells to facilitate this process. As soon as cancer cells have moved to a new location, their growth will be limited unless they can establish a blood supply.

Diffusion of oxygen and nutrients into a collection of cells only permits growth of spherical colonies smaller than a few hundred microns. Larger growth requires the formation of new tumoral blood vessels. Successful cancers can elaborate growth factors such as vascular endothelial growth factor to stimulate angiogenesis (new blood vessel growth).

Cell Cycle Regulation and Anti-Cancer Drugs:

Normal cells have regulated cell cycles composed of the following phases: Quiescent phase [G0], growth phase [G1, S, G2] and mitotic phase [M] with checkpoints and a regulated process of programmed cell death (apoptosis). The G1/S checkpoint is involved in most malignancies. This point is referred to as the restriction point and is a point of irreversible progression towards cell division. Cells will normally continue proliferation in earlymidG1, unless inhibited by inhibitory signals or growth factor deprivation. There tinoblastoma protein (RB) is a key regulator for irreversible initiation of cell division.

Inactivation of the RB by phosphorylation allows the cell to continue to the S phase. In the event of DNA damage, the ATM (ataxia telangiectasia mutated) signal transduction pathway may act to arrest replication (G1 or G2 phases) or prolong replication (G1, S, G2 phases) for repair of the DNA damage. The ATM pathway phosphorylates MDM2 bound to p53. The dissociated p53 is now able to stop cell cycle progression, synthesize repair enzymes and initiate apoptosis. Apoptosis is the process of programmed cell death during cell development or after cellular injury. Apoptosis can be readily identified on histologic sections by the following features—cell shrinkage, chromatin condensation, formation of cytoplasmic blebs, and phagocytizing macrophages. Cells with irreparable DNA damage are flagged for apoptosis, thereby limiting the potential for uncontrolled cell proliferation. However, in most cancers there is one or more genetic alteration in this G1 checkpoint.

Most antineoplastic agents are classified according to their structure or cell cycle activity—either cell cycle phase-specific or cell cycle phase non-specific:

• Cell cycle phase specific agents act on the cells in a specific phase. They are most effective against tumours that have a large proportion of cells actively moving through the cell cycle and cycling at a fast rate. Rapid cycling ensures that the cell passes through the phase in which it is vulnerable to the drugs’ effects.
• Cell cycle phase non-specific agents are not dependent on the cell being in a particular phase of the cell cycle for them to work—they affect cells in all phases of the cell cycle. Resting cells (phase G0) are as vulnerable as dividing cells to the cytotoxic effects of these agents. As a result, phase non-specific agents have been found to be some of the most effective drugs against slow-growing tumours

Cancer Treatment Drugs:

Depending on the type of cancer and the kind of drug used, chemotherapy drugs may be administered differently. They can be administered orally (oral chemotherapy), or injected into a muscle (intramuscular injection), injected under the skin (subcutaneous injection), or into a vein (intravenous chemotherapy).

In special cases, chemotherapy drugs may be injected into the fluid around the spine (intrathecal chemotherapy). Two or more methods of administration may be used at the same time under certain circumstances.

No matter what method is used, chemotherapy drugs are absorbed into the blood and carried around the body. Of all the methods of chemotherapy drug administration mentioned above, intravenous injection is most commonly useIt is the most efficient way to get the medication into the bloodstream. Oral chemotherapy is more convenient and does not require any specialized equipment. In chemotherapy, cancer patients may be given one or several drugs from the available anti-cancer drugs. Since different chemical agents damage cancer cells in different ways and at different phases in the cell cycle, a combination of drugs is often employed to increase the cancerous cell-killing effectiveness. This is called combination chemotherapy.

The different types of chemotherapeutic drugs used are:

1. The Cytotoxics:

1. Alkylating agents: Alkylating agents were among the first anti-cancer drugs and are the most commonly used drugs in chemotherapy today. Alkylating agents act directly on DNA, causing cross-linking of DNA strands, abnormal base pairing, or DNA strand breaks, thus preventing the cell from dividing. Alkylating agents are generally considered to be cell cycle phase nonspecific, meaning that they kill the cell in various and multiple phases of the cell cycle. Although alkylating agents may be used for most types of cancer, they are generally of greatest value in treating slow-growing cancers. Alkylating agents are not as effective on rapidly growing cells. Examples of alkylating agents include chlorambucil, cyclophosphamide, thiotepa, and busulfan.
2. Antimetabolites: Antimetabolites replace natural substances as building blocks in DNA molecules, thereby altering the function of enzymes required for cell metabolism and protein synthesis. In other words, they mimic nutrients that the cell needs to grow, tricking the cell into consuming them, so it eventually starves to death. Antimetabolites are cell cycle specifiAntimetabolites are most effective during the S-phase of cell division because they primarily act upon cells undergoing synthesis of new DNA for formation of new cells. The toxicities associated with these drugs are seen in cells that are growing and dividing quickly. Examples of antimetabolites include purine antagonists, pyrimidine antagonists, and folate antagonists.
3. Plant alkaloids: Plant alkaloids are antitumor agents derived from plants. These drugs act specifically by blocking the ability of a cancer cell to divide and become two cells. Although they act throughout the cell cycle, some are more effective during the S- and M-phases, making these drugs cell cycle specifi Examples of plant alkaloids used in chemotherapy are actinomycin D, doxorubicin, and mitomycin.
4. Antitumor antibiotic: Antitumor antibiotics are cell cycle nonspecifiThey act by binding with DNA and preventing RNA (ribonucleic acid) synthesis, a key step in the creation of proteins, which are necessary for cell survival. They are not the same as antibiotics used to treat bacterial infections. Rather, these drugs cause the strands of genetic material that make up DNA to uncoil, thereby preventing the cell from reproducing. Doxorubicin, mitoxantrone, and bleomycin are some examples of antitumour antibiotics.

2. Targeted Therapies:

Targeted therapy implies drug treatment directed at a particular tumour cell biologic characteristiExamples include expression of the estrogen receptor or overexpression of the HER2 gene in breast cancer, driver mutations in lung cancer, Philadelphia chromosome positivity in chronic myeloid leukemia and acute lymphoblastic leukemia, CD20 positivity in nonHodgkin lymphomas.

3. Immunotherapy:

There have been many attempts to develop vaccines, cytokines, and antibodies to treat cancer immunologically. The concept of using the immune system to treat cancer is the basis of immunotherapy. The human body clearly can generate an immune response to cancers. A biopsy of a cancerous tissue will frequently show a large number of tumor infiltrating lymphocytes (TIL) within the tumor. Some studies have correlated the presence of TIL with better outcomes in some cancers (melanoma, breast). However, despite the presence of an immune response, most cancers evade immune surveillance. One mechanism by which this is accomplished is using checkpoints on regulatory T cells to shutdown the immune response. Antibodies have been developed that inhibit these checkpoints and have been successfully used in the treatment of cancers like melanoma, lung cancer, head and neck cancers, lymphomas, etc.

Role of Medical Oncology:

Medical oncology is the branch of internal medicine that specializes in the treatment of cancer in adult patients and are the physicians who prescribe chemotherapy. Anti-cancer drugs can work by mobilizing the immune system (e.g. interleukin-2, ipilumumab), blocking hormones (e.g. tamoxifen), interrupting intracellular pathways (e.g. temsirolimus), or mutating DNA (e.g. nitrogen mustard) to list a few of the actions. The side effects from these anti-neoplastic agents can range from life-threatening bone marrow suppression to emotionally distressing alopeciAnd hence it should be appreciated that there are different indications, mechanisms, and toxicities for each agent.

The common indications for chemotherapy are:

1. Neoadjuvant chemotherapy—chemotherapy administered before the definitive treatment. For example, chemotherapy given before surgery (in breast cancer, ovarian cancer) or radiation therapy (head and neck cancer).
2. Adjuvant chemotherapy—chemotherapy administered after the definitive treatment. For example, chemotherapy given after surgery (after colonic carcinoma resection or gastric carcinoma resection).
3. Definitive chemotherapy—chemotherapy administered as the primary modality of treatment. For example, chemotherapy given in lymphomas, leukemia.
4. Concurrent chemotherapy—chemotherapy administered along with radiation therapy (concurrent chemoradiotherapy in cervical or head and neck cancer).
5. Palliative chemotherapy—chemotherapy administered for palliation. For example, chemotherapy given in advanced lung cancer or advanced breast cancer.
6. Metronomic chemotherapy—chemotherapy administered in small doses given at regular intervals to avoid toxicities. For example, oral chemotherapy given in head and neck cancers.
7. Targeted chemotherapy—chemotherapy administered against a specific target. For example, anti-Her2/ neu chemotherapy in breast cancer, Rituximab in lymphomas.

Early Detection Of Cancer And Multidisciplinary Approach In the Management Of Cancer

Multidisciplinary Approach in the Management of Cancer:

Cancer is to a large extent avoidable. Many cancers can be prevented and others can be detected early in their development, treated and cureEven with late stage cancer, the pain can be reduced, the progression of the cancer slowed, and patients and their families can be helped to cope. A comprehensive cancer management approach is to implement the four basic components of cancer care—prevention, early detection, diagnosis and treatment, and palliative care.

Multidisciplinary cancer care has an established position internationally and has been recommended by cancer organizations, governments, and learned societies as best practice in cancer care. Multidisciplinary team (MDT) focuses on patient-centered, specialized, and integrated multidisciplinary care, which involves professionals with expertise in all of the major treatment modalities and those skilled in providing appropriate support. All of the professions and disciplines involved in cancer care are included in this concept, including the doctors, cancer nurses, and the many professions that are allied to the provision of cancer management. In an effective MDT, everyone works together to manage individual patients and thus serve as a key resource for the development of strategies for cancer services locally, regionally, and nationally.

Concept of Best Cancer Practice:

Effective prevention (lifestyle, vaccination, public health, etc.) Well-managed screening programs (cervix, breast, colorectal cancer [CRC]).

Prompt diagnosis and rapid referral.

Prompt access to best care.

Patient-centered, specialized, and integrated multidisciplinary care in:

• Surgery
• Radiotherapy
• Chemotherapy
• Biologic therapy
• Psychosocial and survivorship care
• Palliative care at all stages

Access promoted to good care for socially disadvantaged groups.

Research and innovation as a core part of the work of the cancer care team.

Practical Applications:

• MDTs caring for patients with cancer can improve patient outcomes by reviewing their organization, processes, and the quality of their decisions regularly and seeking to continuously improve their practice.
• MDTs caring for patients with cancer can improve patient outcomes by recruiting patients into a clinical trials portfolio.
• MDTs caring for patients with cancer can improve patient outcomes by updating their required inputs from molecular pathology each year.
• MDTs caring for patients with cancer can improve patient outcomes by having a policy for patient engagement in individual care and in policy development for the team.
• MDTs caring for patients with cancer can improve patient outcomes by exploring, initially in pilot form, the use of PROM data to assist in patient evaluation and monitoring.

Cancer Screening:

Diagnosing symptomatic cancer earlier is a feasible and cost-effective strategy, that can contribute to better clinical outcomes and improve patient experience. Effective asymptomatic detection (screening) is currently only available for a few cancers, and even in countries with established population-based screening programs, the majority of patients with cancer are diagnosed following symptomatic presentation. In lowresource settings where screening programs are not available or feasible, early diagnosis (also known as clinical downstaging) strategies can support their introduction by improving clinical pathways and building diagnostic capacity.

Early diagnosis programs consist of supporting prompt help-seeking among symptomatic individuals and/or enabling timely access to diagnosis and treatment. Public education campaigns aiming to raise awareness of cancer and its symptoms and signs among the general population have been conducted in many countries. The timeliness of cancer diagnosis and treatment in symptomatic patients has been conceptualized as a series of intervals starting from symptom onset.

Local or contextualized epidemiological knowledge about the incidence, mortality, and survival associated with different cancers in a given setting can inform the prioritization of cancer types when designing an early diagnosis program.

The early diagnosis program framework comprises four components:

• Conduct of a need assessment (based on cancer site–specific statistics) to identify the cancers that may benefit most from early diagnosis in the target population.
• Consideration of symptom epidemiology to inform prioritization within an intervention.
• Identification of factors influencing prompt helpseeking at individual and system level to support the design and evaluation of interventions.
• Appraisal of factors influencing the health systems’ capacity to promptly assess patients.

Prevention of cancer especially when integrated with the prevention of chronic diseases and other related problems (such as reproductive health, hepatitis B immunization, HIV/AIDS, occupational and environmental health), offers the greatest public health potential and the most cost-effective long-term method of cancer control. There is sufficient knowledge now to prevent around 40% of all cancers.

Most cancers are linked to tobacco use, unhealthy diet, or infectious agents. Early detection detects (or diagnoses) the disease at an early stage, when it has a high potential for cure (e.g. cervical or breast cancer). Interventions are available which permit the early detection and effective treatment of around one-third of cases.

There are two strategies for early detection:

• Early diagnosis, often involving the patient’s awareness of early signs and symptoms, leading to a consultation with a health provider—who then promptly refers the patient for confirmation of diagnosis and treatment.
• National or regional screening of asymptomatic and apparently healthy individuals to detect precancerous lesions or an early stage of cancer, and to arrange referral for diagnosis and treatment.

Screening:

Certain tests help find specific types of cancer before signs or symptoms appear.

This is called screening. The main goals of cancer screening are to:

• Reduce the number of people who die from cancer
• Reduce the number of people who develop the disease

In general, the benefit of cancer screening derives from detecting cancer in earlier and more treatable stages, and thereby, reducing mortality from cancer. In addition, for some cancer types and screening modalities, such as endoscopic screening for colorectal cancer and Papanicolaou (Pap) smears for cervical cancer, screening can also prevent the occurrence of cancer by identifying and removing cancer precursors. Screening may also reduce cancer morbidity when the treatment for earlier-stage cancer is associated with fewer side effects than the treatment for advanced cancers.

Each type of cancer has its own screening tests. Some types of cancer currently do not have an effective screening methoDeveloping new cancer screening tests is an area of active research.

The RCT is the gold standard for assessing the effectiveness of a cancer screening modality. In a randomized controlled trial (RCT) of cancer screening, the primary outcome is typically cancer-specific mortality, defined as the rate of death from the cancer of interest. Overall mortality is not used as the primary endpoint in cancer screening trials because, since deaths from the cancer of interest will be a small fraction of all deaths, there is too much “noise” from non-relevant deaths and the trial would require enormous sample size to be adequately statistically powereThe reduction in mortality that is attributable to screening is often difficult to assess unless there is a dramatic effect, such as with cervical cancer, where the screening modality reduced incidence and very sharply reduced mortality.

Colorectal cancer screening also reduces cancer incidence, although the effects to date have not been as dramatic as for cervical cancer screening. Researchers must often rely on observational or population-level studies to help assess screening benefits. Two common related biases in nonrandomized studies of screening are lead time bias and over-diagnosis bias. Early detection through screening implies an advancement in the time of diagnosis of the cancer from what would have otherwise occurred in the absence of screening. The concept of “lead time” refers to the length of this period of time advancement.

Since diagnosis is advanced and before any symptoms, it is possible that, in the absence of screening, clinical diagnosis would never have occurred, either due to the inherent indolence of the cancer or due to competing causes of death. This phenomenon of screening detecting a cancer that never would have otherwise become clinically apparent is known as overdiagnosis.

Both over-diagnosis and lead-time are theoretical concepts, in that they can generally not be observed in a given individual but can be estimated statistically in populations. Lead time and overdiagnosis can lead to scenarios in observational studies where screening appears to be beneficial even though the modality may actually have no effectiveness in reducing mortality from the cancer.

Another bias in evaluating the effect of screening is selection bias. This issue arises when one examines the (cancer-specific) mortality rate among a group undergoing screening to that in a group not undergoing screening or to population-wide statistics. Since those who choose to be screened may be different with respect to the incidence of and survival from the cancer of interest, these underlying factors, and not the screening itself, may be contributing to any observed differences in mortality rates between the screened and nonscreened (or population-wide) group.

Breast Cancer:

Mammography: Mammography is a type of X-ray specifically designed to view the breast. The images produced by mammography (mammograms) can show tumors or irregularities in the breast.

Clinical breast examination: A medical professional looks and feels for any changes in the breast’s size or shape. The examiner also looks for changes in the skin of the breasts and nipples.

Breast self-examination: During this exam, a woman looks and feels for changes in her own breasts. If she notices any changes, she should see a doctor.

Magnetic resonance imaging (MRI): An MRI is not regularly used to screen for breast cancer. But it may be helpful for women with a higher risk of breast cancer, young age (<40 years), those with dense breasts.

Cervical Cancer:

Human papillomavirus (HPV) testing: Cells are scraped from the outside of a woman’s cervix. These cells are tested for specific strains of HPV. Some strains of HPV are more strongly linked to an increased risk of cervical cancer. This test may be done alone or combined with a Pap test. An HPV test may also be done on a sample of cells from a woman’s vagina that she can collect herself.

Pap test: This test also uses cells from the outside of a woman’s cervix. A pathologist then identifies any precancerous or cancerous cells. A Pap test may be combined with HPV testing.

Colorectal Cancer:

• Colonoscopy: A flexible, lighted tube called a colonoscope is inserted into the colon and the entire colon is inspected for polyps or cancer.
• Sigmoidoscopy: A flexible, lighted tube called a colonoscope is inserted into the colon and the entire colon is inspected for polyps or cancer.
• Fecal occult blood test (FOBT): Test finds blood in the feces, or stool, which can be a sign of polyps or cancer.
• There are two types FOBT: Guaiac and immunochemical.
• Double contrast barium enema: This is an X-ray of the colon and rectum. The barium enema helps the outline of the colon and rectum stand out on the X-rays. This test is used to screen people who cannot have a colonoscopy.
• Stool (Fecal) DNA tests: This test analyzes DNA from a person’s stool sample to look for cancer. It uses DNA changes found in polyps and cancers.

Head and Neck Cancers

General health screening exam. The doctor looks in the nose, mouth, and throat for abnormalities and feels for lumps in the neck. Regular dental check-ups are also important to screen for head and neck cancers.

Lung Cancer:

Low-dose helical or spiral computed tomography (CT or CAT) scan: A CT scan takes X-rays of the inside of the body from different angles. A computer then combines these images into a detailed, 3-dimensional image that shows any abnormalities or tumors.

Prostate Cancer:

• Digital rectal examination (DRE): A DRE is a test in which the doctor inserts a gloved lubricated finger into a man’s rectum and feels the surface of the prostate for any irregularities.
• Prostate-specific antigen (PSA) test: This blood test measures the level of a substance called PSPSA is usually found at higher-than-normal levels in men with prostate cancer. But a high PSA level may also be a sign of conditions that are not cancerous like urinary tract infection, etc.

Skin Cancer:

• Complete skin exam: A doctor checks the skin for signs of skin cancer.
• Skin self-examination: People examine their entire body in a mirror for signs of skin cancer. It often helps to have another person check the scalp and back of the neck.
• Dermoscopy: A handheld device to evaluate the size, shape, and pigmentation patterns of skin lesions. Dermoscopy is usually used for the early detection of melanom

Advantages of Screening:

Risks of screening:

There are documented harms from screening as follows:

• The possibility of serious test-related complications, which may be immediate (e.g. perforation with colonoscopy) or delayed (e.g. potential carcinogenesis from radiation exposure).
• A false-positive screening test result, which may cause anxiety and lead to additional invasive diagnostic procedures.
• Over-diagnosis, which occurs when screening procedures detect cancers that would never become clinically apparent in the absence of screening.
• Increased testing with additional tests that a person may not need because of over-diagnosis and false positives. These tests can be physically invasive, costly, and can cause unnecessary stress and worry

Multiple Choice Questions

Question 1. The following statements about radiation are correct except:

1. Fractional radiation reduces the acute effects of single dose of radiation on normal tissues
2. Cells in mitosis and G2 phase are most sensitive to radiation
3. Oxygen concentration within cells is directly proportional to the radiation dose required to kill them
4. Standard dose of radiation is 180–200 cGy per day and 5 per week over 4–6 cycles

Answer: 3. Oxygen concentration within cells is directly proportional to the radiation dose required to kill them

Question 2. A dose-response curve for radiation is of which shape?

1. Sigmoidal
2. Linear-rising
3. Bell-shaped
4. Irregular

Answer: 1. Sigmoidal

Question 3. The following are the principles of brachytherapy except:

1. It is a type of method of delivery of ionising radiation from sources inside or close to the tumour
2. External RT is used to deliver a higher dose (boost) to treat the primary site while brachytherapy treats the regional spread
3. It is highly localised, specific to a given tumour volume
4. It has a high dose rate, given as continuous RT in a single course

Answer: 2. External RT is used to deliver a higher dose (boost) to treat the primary site while brachytherapy treats the regional spread

Question 4. 1 cGy is:

1. 1 rad
2. 10 rad
3. 100 rad
4. 1000 rad

Answer: 1. 1 rad

Question 5. The most commonly used chemotherapeutic agent with radiation for head and neck cancers is:

1. Vincristine
2. Doxorubicin
3. Cisplatin
4. Etoposide

Answer: 3. Cisplatin

Question 6. Which of the following statements regarding chemotherapy adjuvant to radiotherapy is false?

1. Agent of choice will have minimum toxic effects on the organs included in the radiation target volume
2. Neoadjuvant chemotherapy refers to 1–3 courses of CT after definitive RT
3. Adjuvant CT refers to a course after completion on definitive RT
4. Intrathecal CT is a prophylactic measure to prevent CNS metastasis in cancers like ALL or high grade lymphomas

Answer: 2. Neoadjuvant chemotherapy refers to 1–3 courses of CT after definitive RT

Question 7. IMRT refers to:

1. Intensity-modified radiation therapy
2. Intensity-modulated radiation therapy
3. Intensive method of radiation therapy
4. Intravascular method of radiation therapy

Answer: 2. Intensity-modulated radiation therapy

Question 8. Intra-arterial brachytherapy uses which of the following?

1. Technetium-99
2. Yttrium-90
3. Iodine-123
4. Cobalt-60

Answer: 2. Yttrium-90

Question 9. The following is true about electron beam therapy except:

1. The source is mainly a linear accelerator
2. Most useful range is 6–20 Mev
3. Deeply situated tumours at a depth of >5 cm are treated with this
4. Provides dose uniformity within the target volume

Answer: 3. Deeply situated tumours at a depth of >5 cm are treated with this

Question 10. The following is true about postoperative RT:

1. Exact disease extent is known and treatment can be individualised
2. Postoperative complications, especially wound healing is affected
3. Operative margins are ill-defined
4. Potential for unnecessary radiation increases

Answer: 1. Exact disease extent is known and treatment can be individualised