Part III Management of the Side Effects of Chemotherapy and Radiotherapy

Part III

 

Chapter 1

How to Cope with the Side Effects 

Three Types of Side Effects

    In general, side effects from chemotherapy and radiotherapy can be divided into three types. The first is a set of physiological responses, which are acute and the least concerning, including appetite loss, nausea and vomiting, weakness and fatigue, as well as flu-like symptoms; all of these can be managed by specific actions.

Fig. 3.1  Common cell types in a cell renewal system 

The second type of side effects is more severe and may damage cells in renewal tissues. There are a number of such cell renewal tissues in the body encompassing the hematopoietic system, the gastrointestinal tract, skin, hair, gonads, and cornea. Fig. 3.1 shows the common cell types in a cell types in a cell renewal system. The first and basic cell type is the stem cell – destroy all of these and the tissue gradually disappears. These cells are especially sensitive to both radiation and chemotherapeutic agents, and more so when they are proliferating. If over 99.9% of the stem cells are destroyed, the renewal tissue can’t recover by itself and the host will die. If stem cells are not totally destroyed, stem cell transplant and some protective agents can ameliorate some of the damage. The “committed” stem cells and differentiating cells (which may require proliferation) are also sensitive to chemotherapy and radiotherapy since they are proliferating just like the cancer cells. Finally, the differentiated cells such as platelets and red blood cells are resistant to chemotherapy. However, since the differentiated cells have a specific half-life, they are “used up” and may not be replaced as the stem cells and differentiating precursor cells have been destroyed. 

The third type of side effects is direct damage to cells in major organs such as liver, heart, and brain. These are non-proliferating cells, and like the differentiated cells discussed above and relatively insensitive. However, some drugs do have selective toxicity to specific organs such as anthracyclines and cardiac toxicity.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Part III Management of the Side Effects of Chemotherapy and Radiotherapy

Part III

 

Chapter 1

How to Cope with the Side Effects 

The major side effects of chemotherapy and radiotherapy include tissue/organ injury which occasionally may be fatal. In addition, these side effects may prevent doctors from delivering the prescribed dose of therapy according to the predetermined schedule in the cancer treatment plan. It is important to understand that the expected outcome from therapy is based on delivering treatment at the dose and schedule according to the well-designed and predetermined treatment plan. In other words, not only are the side effects of chemotherapy or radiotherapy undesirable, they may also limit a patient’s ability to accept the complete therapeutic regimen (both dose and schedule) to achieve the best outcome.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

PART II

Chapter 3

Modern Technologies in Radiotherapy (Cont'd)

4. Improvement of radiotherapy by using radiomitigators

Different from radioprotectors, which need to be administered either before or during radiotherapy, radiomitigators can be administered after radiation treatment. Radiomitigation can also be very useful in term of national defense with the increasing global threat of terrorists, such as potential radiological attack by dirty bombs.

Currently, there is not an FDA approved radiomitigator. However, there are a number of drug candidates under investigation as radiomitigator.

 © Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

PART II

Chapter 3

Modern Technologies in Radiotherapy (Cont'd)

Special Announcement related to this topic, radioprotectors.

We have just been allowed a patent by the US Patent and Trademark Office (US PTO). This patent is related to a new radioprotector. Further details will be announced after this patent is officially issued in the near future.

 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

 PART II

Chapter 3

Modern Technologies in Radiotherapy (Cont'd)

3. Improvement of radiotherapy by using radioprotectors 

Radioprotection is another important approach in radiotherapy. Basically, a therapeutic agent, radioprotector, is administered to a patient before the patient is treated by radiotherapy. In other words, radioprotectors protect normal tissues against radiation-induced side effects. Ideally, radioprotectors produce or stimulate certain biological reactions/products which then counteract the adverse effects caused by radiation. 

Unfortunately, there has not been any significantly improved radioprotector since the discovery and approval of a popular broad-spectrum radioprotective drug, amifostine (Fig. 2.3), by the FDA. Interestingly, amifostine was originally approved to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and non-small cell lung cancer. However, while nephroprotection was observed, amifostine also formed chelation with cisplatin and reduced its anticancer activity. Therefore, its indication for chemoprotection in cisplatin treatment in non-small cell lung cancer was withdrawn in 2005.

Fig. 2.3.   Structure of amifostine (WR2721) and its metabolite

 

 More details about amifostine and other radioprotectors are described in Part III.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

 PART II

Chapter 3

Modern Technologies in Radiotherapy (Cont'd)

2. Improvement of radiotherapy by using radiosensitizers

A radiosensitizer (also referred to as a radiosensitizing agent) is a pharmaceutical agent that makes tumor cells more sensitive to radiation, thus, increasing the efficiency of radiotherapy. For example, oxygen is known to increase tumor sensitivity to radiation by forming free radicals that can damage DNA. 

As a solid tumor continues to grow, some cancer cells outgrow their blood supply and become sufficiently removed from their capillaries to become hypoxic (lack of oxygen). As a result, cancer cells survive by another mechanism called glycolysis. Glycolysis is a process in which glucose is converted into pyruvate by an oxygen-independent metabolic pathway; the process produces energy which is then stored in the form of ATP (adenosine triphosphate) for anaerobic cancer cells. In the presence of oxygen, ATP is formed through oxidative phosphorylation. 

The process of glycolysis further results in excess lactic acid, which makes solid tumor more acidic (pH can be as low as 6.2). In general, cancer cells under acidic condition (mainly due to hypoxia) are more resistant to killing by radiotherapy and some cancer drugs. 

      Currently, there are a number of agents being investigated as potential radiosensitizers. Some examples of radiosensitizers are shown in Part III. 

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

 PART II

Chapter 3

Modern Technologies in Radiotherapy (Cont'd)

1. Improvements on the technical aspects of radiotherapy 

Generally, radiation oncologists attempt to reduce the injury to normal tissues surrounding the target tumor by limiting (or blocking) the radiation field. In recent years, a number of significant technical developments and modifications in radiotherapy have been developed in order to increase the efficacy of radiotherapy and/or reduce radiotherapy-induced injury. These technology improvements include using multiple ports, higher radiation doses, interstitial brachytherapy, stereotactic radiosurgery, and TomoTherapy. In general, therapists use these approaches in attempts to increase the radiation dose to the tumor tissue while decreasing the dose to the surrounding normal tissue(s). The main goals are to enhance/maintain the therapeutic effect while minimizing the damages to normal tissues. 

A representative example of these newer technologies is stereotactic radiotherapy. Stereotactic radiotherapy utilizes small fractions of high-dose radiation (as compared to conventional dose) from different angles to destroy tumor tissue. By giving multiple radiation doses from different angles, it can improve the radiotherapy outcome while minimizing potential side effects on normal tissues, especially the skin. Stereotactic radiotherapy is now frequently used to treat brain tumors and other types of solid tumors. 

A specific form of stereotactic radiotherapy used for brain tumors is called stereotactic surgery, which utilizes high dose radiation (x-ray or gamma ray) to precisely focus on the specific area in the brain to destroy tumor tissues in the brain, very similar to surgery, thus often referred to as radiation surgery. In this treatment, the dose and the treatment area have to be precisely coordinated to ensure that normal tissues in the proximity suffer the least damage by the high dose radiation. It is also called fractionated stereotactic radiosurgery wherein the total dose of radiation is divided into several doses and delivered in several days. 

Another popular new technology is called TomoTherapy. It is a computed tomograph (CT)-guided intensity modulated radiation therapy (IMRT) that delivers radiation to the tumor slice-by-slice, which is different from other forms of external beam radiation therapy in which the entire tumor volume is irradiated. TomoTherapy is essentially an image-guided radiation therapy (IGRT). The “beam on” time for TomoTherapy (3 to 5 minutes) is similar to normal radiotherapy. However, it does require additional daily CT to precisely locate the tumor because tumor size and position may shift due to the shrinkage over time. The daily CT will help the operator in directing the radiation beam to modify the treatment (adaptive radiotherapy). TomoTherapy has been used in many solid tumors including prostate cancer, lung cancer, as well as head and neck cancer. 

In recent years, stereotactic radiotherapy is being combined with TomoTherapy. Right before the radiotherapy procedure, a patient is positioned on an examination table and a high-resolution CT scan is used to determine the precise location, size, and shape of the tumor. The data is then transferred to the computing system wherein an exact treatment plan is defined in real time. Once the patient is positioned, the radiation source is rotated and/or orientated by a computer to different positions/angles, and a predetermined dose of radiation is targeted at the tumor while sparing the healthy tissues. Commercially, several advanced radiotherapy systems utilizing similar principle have been developed and used. Examples of modern radiotherapy systems include Discovery CT590 RT and Optima CT580 made by GE Healthcare, and CyberKnife® made by Accuray. The most recent comprehensive radiosurgery system, Edge™, is made by Varian Medical Systems.  Edge™ is just entering the market and there are only few units installed in the United States. It is a dedicated system for performing advanced radiosurgery using new real-time tumor tracking technology.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 3 - Modern Technologies in Radiotherapy

 PART II

Chapter 3

Modern Technologies in Radiotherapy

     Many approaches have been employed by the medical/pharmaceutical community to enhance the therapeutic effect of radiotherapy and/or to protect normal tissues or ameliorate tissue injury induced by radiotherapy. In general, there are four major approaches: (1) improvements/modifications on technical aspects of radiotherapy, (2) use of radiosensitizers to enhance the killing of radio-resistant cancer cells, (3) use of radioprotective agents to protect normal tissues and/or reduce the side effects, and (4) use of radiomitigators to speed up the recovery of normal tissues from injury induced by radiotherapy.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

Additional information about the side effects of radiotherapy

Because a human body is a delicate and complicated biological system, and the inter-communication among different organs are even more complex, some side effects are inter-connected and may not be clearly separated from one another. Let’s use some examples for further illustration.

Cancer patients treated by high dose radiation onto specific organ may suffer organ damages in addition to other side effects (hair loss, diarrhea, etc.). Let’s look at the radiotherapy on liver cancer as a specific example. Patients with liver cancer, when treated by ionizing radiation, may suffer from liver damage and/or liver function reduction.

There are several reasons why organ damages occur after radiation therapy. The obvious reason is that liver cells damaged by DNA will result in the damage of liver tissue through mechanisms such as programmed cell death (apoptosis). The other important reason is that certain cytokines, such as TNF-a, in liver and blood are often markedly induced by radiation therapy. As described before, abnormally elevated levels of TNF-a will kill the surrounding cells (no matter cancer cells or normal cells), and will cause certain liver damage. 

Our experimental results showed that radiation in mouse liver induced liver damage (reflected by elevated serum levels of both aspartate transaminase (AST) and alanine transaminase (ALT), and the liver damage is in correlation with increased levels for serum TNF-a induced by irradiation. Pre-treatment of mice with a small-molecule TNF-a modulator UTL-5d (Fig. 2.2) effectively reduced TNF-a secretion and resulted in marked reduction of ALT/AST levels. This implies that TNF-a may play an important role in damaging the liver and UTL-5d compound may be a potential agent for radioprotection.

                                                                    Fig. 2.2   Structure of UTL-5d

    In order to reduce the side effects induced by radiotherapy, there are several general strategies being employed as described in the next chapter. 

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

4. Other side effects of radiotherapy

The medium- and long-term side effects of radiotherapy that one can see or feel depend on the tissues/organs that receive the radiation. With today’s technological improvement, these side effects can be significantly reduced.
 Because radiotherapy is being used in different types of cancers and every patient’s situation is different, the side effects could vary from patient to patient. Some of the more common side effects from radiotherapy are described below:

Fatigue or tiredness

        Fatigue is among the most common symptoms of radiotherapy. Lack of energy and an overtired feeling are common symptoms. Depending on the type of cancer and the regimen of the radiation treatment, the degree of fatigue may be different. Usually, patients should gradually recover from the lack of energy several weeks after the completion of radiotherapy. 

Dryness

        Radiotherapy on patients with head and neck cancer often causes the release of free radicals in saliva glands, resulting in lack of saliva (abnormal dryness of the mouth or xerostomia). Radiation therapy may also cause dry eye (xerophthalmia). Similarly, vaginal mucosa may be dry after pelvic irradiation.

Fibrosis

        Fibrosis is the development of excessive fibrous connective tissue in an organ or tissue. As a reactive response to the high radiation energy, irradiated tissues tend to be inflamed and gradually become less elastic. Overtime, certain irradiated area may gradually become fibrosis. This happens more often for lung cancer patients being treated with radiotherapy.

Cancer (secondary malignancy)

        Because radiation can alter certain DNA, it is also a potential cause of cancer, albeit a low probability. Some patients may develop secondary malignancies several years after receiving a course of radiation treatment. In most cases, this risk is greatly outweighed by the reduction of the primary cancer.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

3. Activation of immunologic responses

    In addition to producing the direct DNA damage, radiation can also produce a lot of free radicals, including reactive oxygen species (ROS), and cause indirect damages to normal tissues/organs.  The delicate immune system can also be disturbed by this oxidative stress, causing extraordinary number of immunological responses, including the abnormal release of many cytokines.

    Cytokines are regulatory proteins released by cells of the immune system. It has been reported that a number of cytokines may be induced by radiation, including tumor necrosis factor alpha (TNF-α), IL-1, IL-4, IL-5, IL-6, IL-8, IL-10, and transforming growth factor beta (TGF-β).  The alteration of cytokine levels in blood, skin, or other tissues can cause a number of pharmacological responses. 

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

2. Damage to cell renewal

      The following side effects are under a class called cell renewal effects.

Damage to bone marrow 

Bone marrow is the flexible tissue in the hollow interior of bones. It is responsible for the production of blood cells, including RBCs, WBCs, and platelets. If a person is exposed to a high dose of radiation for too long (especially on pelvis, chest and other bones), one can suffer bone marrow damage. As a result of radiotherapy, a patient may suffer from low WBC count (neutropenia or leukopenia), low RBC count (anemia), and/or low platelet count (thrombocytopenia). As explained in the previous chapter, neutropenia may increase a patient’s chance of infection, anemia may cause fatigue, and thrombocytopenia can increase a patient’s risk of bruising and bleeding.

 On the other hand, radiation damage to bone marrow is not completely negative. For patients that require bone marrow transplantation, a high dose TBI becomes a positive tool in that unhealthy bone marrow cells are “wiped out” by high-dose radiation before a patient receives healthy bone marrow cells or cord blood cells. 

Hair loss (alopecia)

        Radiotherapy often causes hair loss on the body part being treated [35, 36]. However, hair loss from radiotherapy is usually limited to the area treated by the radiation. For patients who receive radiotherapy for brain cancer, the most pronounced side effect may be hair loss. In this case, radiation-induced hair loss could be permanent; this is different from chemotherapy on other part of the body wherein hair loss is more likely temporary.

Anemia  

        Depending on the dose and the time of treatment, radiotherapy may or may not cause anemia for cancer patients. Many patients experience anemia at some point during treatment; in serious situations, it may cause aplastic anemia.

 Aplastic anemia is when the hematopoietic stem cells in bone marrow are seriously damaged. As a result, all blood cells are not adequately produced, and could be fatal in some cases. One of the most important pioneers in radioactivity, Marie Curie, died from aplastic anemia which was believed to have resulted from her long-term exposure to the radioactive materials she studied.

Diarrhea

 

  When the lining of mouth, stomach, and intestines are injured by radiotherapy, it may cause diarrhea. It is common to have diarrhea during or after radiotherapy treatment on the stomach or abdomen. The diarrhea can gradually get worse as the treatment goes on.  Once the treatment ends, the diarrhea normally goes away gradually over a couple of weeks, but for some people it may take a little bit longer.

Skin damage

        Radiotherapy can induce tanned (hyperpigmentation), irritated, peeling or burned skin. Because recent radiotherapy technology utilizes higher radiation doses, skin damage becomes a problem that happens more often. On the other hand, in the most recent radiosurgery, such as stereotactic radiotherapy, because radiation is applied from different direction, skin damage is significantly reduced.  

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen. 

Radiotherapy and Its Side Effects: Chapter 2 - Side Effects of Radiotherapy

PART II

Chapter 2

Side Effects of Radiotherapy (Cont'd)

1.       Damage to the DNA of normal cells 

 The potential adverse effects of radiotherapy to the DNA of normal cells may result in tissue/organ damage and potentially secondary cancer. This is mainly due to (1) the direct exposure of normal cells to radiation, and (2) the indirect effect from the free radicals generated by radiation, which might result in the modification of certain genes generally referred to mutation. As a result, there is a possibility that certain cancer might be induced in the future, also known as secondary cancer, especially if high radiation dose is used often. 

In recent years, significant technical improvements have been made to greatly reduce this type of potential side effect. Examples of the newer radiotherapy technologies are described in the following chapter.

© Jiajiu Shaw, 2021

Disclaimer: This blog is written solely for informational purposes. It does not constitute the practice of any medical, nursing or other medical professional health care advice, diagnosis, or treatment. All contents posted are extracted from the book, "SIDE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY", prepared by Dr. Jiajiu Shaw, Dr. Frederick Valeriote, and Dr. Ben Chen.