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What is Immunotherapy in cancer

 

Immunotherapy is a type of treatment that uses the body’s own immune system to recognize and kill cancer cells. Cancer cells often can fool the body into not recognizing they are dangerous. If the body can’t tell the difference between cancer cells and healthy cells, cancer cells may be able to “hide” from the immune system. To identify cancer cells as a threat and target them for destruction, immunotherapy uses substances either made by the body or in a laboratory to enhance recognition or effector function of the immune response against the cancer.

 

Different types of immunotherapy exist. Each works in a unique way to slow and stop the growth of cancer cells, stop cancer cells from spreading to other parts of the body and help the immune system work better overall at destroying cancer cells. Some immunotherapy treatments boost the body’s immune system while others train the immune system to attack cancer cells:

 

  • Checkpoint inhibitors are an important part of the immune system due to their ability to keep immune cells from attacking normal cells in the body. Checkpoints are proteins on immune cells that need to be turned on or off to start/stop an immune response. The immune system uses checkpoints to prevent itself from attacking normal cells in the body and deleted immune cells after their functions have been completed, for example following clearance of an infection. But melanoma cells sometimes hijack these checkpoints to avoid being attacked by the immune system. Checkpoint inhibitors target the checkpoint proteins, helping to restore the immune response against melanoma cells.
  • Cytokines are soluble molecules that enable immune cells to communicate with each other. Cytokines work together to make sure that the immune response is of the right strength and length of time.  Laboratory-made versions of cytokines are sometimes used to boost the immune system in people with melanoma.
  • Oncolytic viruses are viruses altered in a laboratory so that they preferentially infect and kill mainly cancer cells. Along with killing the cells directly, the viruses can also alert the immune system to attack the cancer cells.
  • Cancer vaccines are substances that stimulate the immune system to fight infection or disease. Cancer vaccines strengthen the immune system against cancer cells.
  • Nonspecific immune stimulators boost the immune system in a general way to help the immune system attack cancer cells.

 

Certain immunotherapies work well when given alone. Others work better in combination with additional treatment strategies.

 

At present, the clinical use of immunotherapy is largely restricted to the adjuvant treatment of Stage III and systemic treatment of Stage IV melanomas, although there is intense interest in evaluating immunotherapy as neoadjuvant or adjuvant therapy for all stages.

 

Why is Immunotherapy needed?

 

Immunotherapy has the potential to achieve durable clinical responses in some patients. In addition, an improved quality of life may also make immunotherapy an attractive choice for people who have this treatment option. Immunotherapy may be an option for patients to consider because the side effects, although prevalent, may be easier on patients compared to typical chemotherapy-related toxicities, and with appropriate attention, can be simple to manage. The side effect profile differs from other types of cancer therapeutics. Some side effects occur as a result of an overactive immune system, not the destruction of healthy cells, as often occurs with cytototoxic chemotherapy. Because not as many healthy cells are damaged with immunotherapy, some patients have reported a different range of side effects.

 

One limitation to immunotherapy is that it can be very effective in some patients but not in others. Researchers continue to explore why this happens to determine how to improve existing therapies and to develop new ones through clinical trials. Researchers are interested in identifying biomarkers that may be able to better predict which patients are likely to respond to which immunotherapy agents or combinations.

 

Several immunotherapy agents or regimens are currently approved by the FDA for the treatment of melanoma. Other novel treatments that are not yet FDA-approved may be accessible through clinical trials. Discuss the opportunity to participate in a clinical trial with your patients if they have not responded to other therapies or if you feel this may be the best treatment option for them. Provide them with multiple resources, and encourage them to become advocates for their own health by learning about and researching available clinical trials. 

 

How is Immunotherapy given?

 

Different forms of immunotherapy may be given in different ways. These include:

 

  • Intravenous IV): The immunotherapy goes directly into a vein.
  • Oral: The immunotherapy comes in pills or capsules that you swallow.
  • Topical: The immunotherapy comes in a cream that you rub onto your skin. This type of immunotherapy can be used for very early skin cancer.
  • Intravesical: The immunotherapy goes directly into the bladder.

 

How does Immunotherapy work against cancer?

 

As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors don’t contain them.

 

Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:

 

  • Have genetic changes that make them less visible to the immune system.
  • Have proteins on their surface that turn off immune cells.
  • Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells.

 

Immunotherapy helps the immune system to better act against cancer.

 

Side Effects of Immunotherapy

 

Immunotherapy can cause side effects, many of which happen when the immune system that has been revved-up to act against the cancer also acts against healthy cells and tissues in the body. Different people have different side effects. The ones you have and how they make you feel will depend on how healthy you are before treatment, your type of cancer, how advanced it is, the type of immunotherapy you are getting, and the dose.

 

You might be on immunotherapy for a long time, and side effects can occur at any point during and after treatment. Doctors and nurses cannot know for certain when or if side effects will occur or how serious they will be. So, it is important to know what signs to look for and what to do if you start to have problems.

 

Some side effects are common with all types of immunotherapy. For instance, you might have skin reactions at the needle site, which include:

 

  • Pain
  • Swelling
  • Soreness
  • Redness
  • Itchiness
  • Rash

 

You may have flu-like symptoms, which include:

 

  • Fever
  • Chills
  • Weakness
  • Dizziness
  • Nausea or vomiting
  • Muscle or joint aches
  • Fatigue
  • Headache
  • Trouble breathing
  • Low or high blood pressure

 

Other side effects might include:

 

  • Swelling and weight gain from retaining fluid
  • Heart palpitations
  • Sinus congestion
  • Diarrhea
  • Risk of infection
  • Organ inflammation

 

Some types of immunotherapy may cause severe or even fatal allergic and inflammation-related reactions. However, these reactions are rare.

 

What are the types of Immunotherapy?

 

Monoclonal antibodies (mABs)

 

Monoclonal antibodies are laboratory produced antibodies designed to recognise and bind to specific receptors found on the surface of cells. They are derived from natural antibodies, complex proteins derived from a single B cell made by the body’s immunological defence system to recognise and fight foreign invaders such as bacteria and viruses.

 

How they work?

 

A MAB works by recognising and finding specific proteins on cells. Some work on cancer cells, others target proteins on cells of the immune system.

 

Each MAB recognises one particular protein. They work in different ways depending on the protein they are targeting. Trigger the immune system

 

Some MABs trigger the immune system to attack and kill cancer cells.

 

Although cancer cells are abnormal, they develop from normal cells so they can be difficult for the immune system to spot. Some MABs attach themselves to cancer cells, making it easier for the cells of the immune system to find them. This process is called antibody-dependent cell-mediated cytotoxicity or ADCC.

 

Examples of MABS that work in this way include:

 

  • rituximab (Mabthera) – a treatment for chronic lymphocytic leukaemia (CLL) and some types of non Hodgkin lymphoma
  • cetuximab (Erbitux) – a treatment for advanced bowel cancer and head and neck cancer
  • trastuzumab (Herceptin) – used to treat breast cancer and stomach cancer

 

Help the immune system to attack cancer

 

Other MABs work by acting on cells of the immune system. For example, immunotherapies called checkpoint inhibitors block proteins that stop the immune system attacking cancer cells.

 

Checkpoint inhibitors block different proteins, including PD-1 and PD-L1 (programmed death ligand 1). So you might also hear some of these drugs called PD-1 inhibitors or PD-L1 inhibitors.

 

Examples of checkpoint inhibitors include:

 

  • ipilimumab (Yervoy) – a treatment for advanced melanoma
  • nivolumab (Opdivo)
  • pembrolizumab (Keytruda)

 

Nivolumab and pembrolizumab are used to treat different types of cancer, including Hodgkin lymphoma and melanoma.

 

How you have them

 

You have MAB treatment as an injection under the skin (subcutaneous injection), or through a drip (infusion) into a vein. For some drugs, you have your first treatment into your vein, then further treatments as an injection under your skin. 

 

How often you have treatment and how many treatments you need will depend on:

 

  • which MAB you have
  • the type of cancer you have

 

Testing

 

Before you have some types of MAB you might need to have tests using some of your cancer cells or a blood sample to find out whether the treatment is likely to work. These tests look for changes in certain proteins or genes. 

 

You cancer specialist can tell you if this applies to your treatment. This is not the case for all MABs and you don’t always need this test.

 

To test your cancer cells, your specialist needs a sample (biopsy) of your cancer. They might be able to test some tissue from a biopsy or operation you have already had. 

 

Side effects

 

All treatments have possible side effects. These can vary depending on the type of MAB you have. 

 

Allergic reaction during treatment

 

A common side effect of some MABs is an allergic reaction to the drug. This reaction is most likely to happen during treatment and when you first have the treatment. 

 

If this is possible with your drug, you might have paracetamol, a steroid and an antihistamine drug before treatment to prevent a reaction.

 

An allergic reaction can include these symptoms, though you may not have all of them:

 

  • breathlessness
  • fever and chills
  • an itchy rash
  • flushes and faintness

 

Your nurse will monitor you and treat any symptoms if they happen.

 

General side effects

 

Side effects might include:

 

  • skin changes such as red and sore skin or an itchy rash
  • diarrhoea
  • tiredness
  • flu-like symptoms such as chills, fever, dizziness
  • feeling or being sick

Ref:

  • Cancer: Principles and Practice of Oncology (10th edition)
    VT De Vita, TS Lawrence and SA Rosenberg
    Lippincott, Williams and Wilkins, 2015
  • Electronic Medicines Compendium
    Accessed July, 2017
  • Recognizing and managing on toxicities in cancer immunotherapy
    L Yang and others
    Tumour Biology, 2017. Volume 39, Issue 3:1010428317694542
  • State of the art in anti-cancer mAbs
    SM Chiavenna and others
    Journal of Biomed Science, 2017. Volume 24, Issue 15
  • NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy
    W Wang and others
    Front Immunology, 2015. Volume 6, Issue 368

 

Cancer vaccines

 

Vaccines to treat cancer

 

Vaccines are a type of immunotherapy. Research in this area is at an early stage and vaccines are mainly available as part of clinical trials. 

 

What vaccines are?

 

Normally, vaccines help to protect us from disease. They are made from weakened or harmless versions of the disease they are being made to protect us from. This means that they don’t cause the disease.

 

When you have the vaccine, it stimulates the immune system into action. The immune system makes antibodies that can recognise and attack the harmless versions of the disease. Once the body has made these antibodies it can recognise the disease if you come into contact with it again. So you’re protected from it. 

 

Vaccines to treat cancer

 

Researchers are looking at vaccines as a possible treatment for cancer.

 

In the same way that vaccines work against diseases, the vaccines are made to recognise proteins that are on particular cancer cells. This helps the immune system to recognise and mount an attack against those particular cancer cells. These vaccines might help to:

 

  • stop further growth of a cancer
  • prevent a cancer from coming back
  • destroy any cancer cells left behind after other treatments

 

Types

 

Scientists are studying many different types of cancer vaccines and how they work in different ways. More research is needed before they have a full picture of how well this type of treatment works and which cancers it may treat.

 

The following types of cancer vaccines are most commonly under investigation throughout the world:

 

Antigen vaccines

 

These vaccines are made from special proteins (antigens) in cancer cells. They aim to stimulate your immune system to attack the cancer. Scientists have worked out the genetic codes of many cancer cell proteins, so they can make them in the lab in large quantities.

 

Whole cell vaccines

 

A whole cell vaccine uses the whole cancer cell, not just a specific cell protein (antigen), to make the vaccine. Scientists make the vaccine from your own cancer cells, another person’s cancer cells or cancer cells that were grown in the laboratory.

 

Dendritic cell vaccines

 

Dendritic cells help the immune system recognise and attack abnormal cells, such as cancer cells. To make the vaccine, scientists grow dendritic cells alongside cancer cells in the lab. The vaccine then stimulates your immune system to attack the cancer.

 

DNA vaccines

 

These vaccines are made with bits of DNA from cancer cells. They can be injected into the body to make the cells of the immune system better at responding to and destroying cancer cells.

 

Anti idiotype vaccines

 

This vaccine stimulates the body to make antibo dies against cancer cells.

 

References

 

 

Cytokine therapies

 

Cytokines are a group of proteins in the body that play an important part in boosting the immune system. Interferon and interleukin are types of cytokines found in the body. Scientists have developed man made versions of these to treat cancer.

 

The man made version of interleukin is called aldesleukin.

 

How interferon and aldesleukin work

 

Interferon and aldesleukin work in several ways, including:

 

  • interfering with the way cancer cells grow and multiply
  • stimulating the immune system and encouraging killer T cells and other cells to attack cancer cells
  • encouraging cancer cells to produce chemicals that attract immune system cells to them

 

Interferon

 

Interferon is also called interferon alfa or Intron A.

 

Doctors use interferon for several different types of cancer including:

 

  • kidney cancer (renal cell cancer)
  • melanoma
  • multiple myeloma
  • some types of leukaemia

 

You are more likely to have interferon as an injection just under the skin (subcutaneously). Or you might have it into the bloodstream through a drip (infusion).

 

How often you have it depends on which type of cancer you are having treatment for. Most people have interferon 3 times a week. Or you might have it as a daily injection.

 

Aldesleukin

 

Aldesleukin is also called Interleukin 2, IL2 or Proleukin.

 

In cancer care, doctors use it most often to treat kidney cancer. It is also in clinical trials for some other types of cancer.

 

You are most likely to have it as an injection just under the skin (subcutaneously). But you may have it into a vein, either as an injection or through a drip.

 

How often you have this drug depends on which cancer you are being treated for.

 

Side effects of interferon and aldesleukin

 

The side effects of interferon and aldesleukin include:

 

  • a drop in blood cells causing an increased risk of infection, bleeding problems, tiredness and breathlessness
  • flu-like symptoms
  • diarrhoea
  • tiredness and weakness (fatigue)
  • feeling sick
  • loss of appetite

 

Aldesleukin can also cause low blood pressure.

 

Ref:

  • Electronic Medicines Compendium 
    Accessed August 2017
  • Cancer: Principles and Practice of Oncology (10th edition)
    VT De Vita, TS Lawrence and SA Rosenberg
    Lippincott, Williams and Wilkins, 2015
  • Immunotherapy for metastatic renal cell carcinoma
    S Unverzagt and others
    Cochrane Database Syst Review, 2017. Volume 15, Issue 5
  • Recognizing and managing on toxicities in cancer immunotherapy
    L.Yang and others
    Tumour Biology, 2017. Volume 39, Issue 3, 

 

Adoptive T-cell transfer

 

CAR T-cell therapy

 

CAR T-cell therapy is a type of immunotherapy. You might also hear it called a type of adoptive cell transfer.

 

CAR T-cell therapy is a very complex and specialist treatment. With this treatment, a specialist collects and makes a small change to your T cells. These then target the cancer cells. 

 

It is available as a possible treatment for some children with leukaemia and some adults with lymphoma. People with other types of cancer might have it as part of a clinical trial. 

 

T cells

 

To understand CAR T-cell therapy more, it helps to understand what T cells do.

 

White blood cells called lymphocytes play an important part in fighting infection and diseases, including cancer. There are different types of lymphocytes. T cells are one type.

 

T cells move around the body to find and destroy defective cells. When you come into contact with a new infection or disease, the body makes T cells to fight that specific infection or disease. It then keeps some in reserve so that if you come across the infection again your body can recognise it and attack it immediately. 

 

CAR T-cell therapy

 

T cells are good at fighting infection. But it can be difficult for them to tell the difference between a cancer cell and a normal cell. So the cancer cells can hide away and not be recognised.

 

Scientists are trying to find ways to get T cells to recognise cancer cells. One possible way to do this might be CAR T-cell therapy. 

 

What happens

 

With this treatment, you have a sample of T cells taken from your blood. Your medical team do this through a process called apheresis.

 

First you have a tube put into a vein in each arm. One tube removes the blood and passes it into an apheresis machine. The machine separates the different parts of the blood. For CAR T-cell therapy, the machine takes out your T cells. The rest of your blood cells and normal blood fluid go back into your body through the tube in your other arm.

 

In the lab, they change the T cells. You might hear this called genetically engineering the T cell. The T cell is now a CAR T-cell. CAR stands for chimeric antigen receptor. These CAR T-cells are designed to recognise and target a specific protein on the cancer cells.

 

These changed T cells grow and multiply in the lab. Once there are enough cells you have a drip containing these cells back into your bloodstream. The aim is for the CAR T-cells to then recognise and attack the cancer cells.

 

The changes they make in the lab mean that they can stay in your body for long periods of time, recognising and attacking the specific cancer cells. Researchers are still looking into how long they might stay in the body.

 

There are different types of CAR T-cell therapy made by different companies. Examples include:

 

  • tisagenlecleucel (Kymriah) 
  • axicabtagene ciloleucel (Yescarta)

 

Which cancer types?

 

CAR T-cell therapy is available for some children with leukaemia and some adults with lymphoma. This followed decisions by the National Institute for Health and Care Excellence (NICE) in England in December 2018 and January 2019. And decisions by the Scottish Medicines Consortium (SMC) in 2019.

 

Side effects

 

This is a new treatment, so doctors might not know about all the possible side effects yet. Known side effects include:

 

  • cytokine-release syndrome
  • changes in the brain (neurological side effects)
  • no B cells or fewer B cells after treatment with CAR T-cells that target CD19

 

Cytokine release syndrome

 

Cytokines are group of proteins in the body that play an important part in boosting the immune system. CAR T-cell therapy stimulates the immune system to make large amounts of cytokines. It causes symptoms such as:

 

  • fever (high temperature)
  • dizziness due to low blood pressure
  • difficulty breathing

 

This syndrome might happen in the first week of treatment. You can have treatment to reverse the syndrome.

 

Side effects affecting the brain (neurological side effects)

 

Sometimes CAR T-cells cause problems to the brain. Doctors call this neurotoxicity. Symptoms might include:

 

  • headaches
  • altered consciousness
  • becoming confused or disorientated
  • speech changes
  • seizures

 

The treating team monitors you, or your child, closely for any of these changes. The changes might go away on their own or you might need treatment, for example steroids. Treatment depends on the symptoms you, or your child, are experiencing and how serious they are.

 

Ref: 

 

 

NHS England November 2018

 

Radioimmunotherapy

 

What is radioimmunotherapy and how does it work?

 

Radioimmunotherapy (RIT) involves a small amount of radioactive material (radionuclide) — that is combined with a molecule engineered in a laboratory (monoclonal antibody). This monoclonal antibody-radionuclide compound is called a radiopharmaceutical. Monoclonal antibodies are able to recognize and bind to specific features of cells, such as antigens and cell receptors. When injected into the patient’s bloodstream, the radiopharmaceutical attaches to cancer cells, delivering a high dose of radiation to be delivered to the tumor.

 

What conditions are treated with radioimmunotherapy?

 

There are two RIT agents approved by the U.S. Food and Drug Administration (FDA): Zevalin and Bexxar.  Both of these are used to treat patients with B-cell Follicular non-Hodgkin lymphoma (NHL) that has not responded to chemotherapy treatment, although these can be used in some other types of lymphomas or scenarios as a part of the treatment for a patient’s lymphoma. Zevalin, consists of a radioactive molecule Yttrium-90 (Y-90) combined with the monoclonal antibody ibritumomab tiuxetan; Bexxar, is a compound consisting of Iodine-131 (I-131) and tositumomab.  Currently, only Zevalin (Y-90 Ibritumomab tiuxetan) is available on the market.

 

How is radioimmunotherapy performed?

 

Patients typically undergo one or two sessions of RIT. A team of medical professionals, including an oncologist, a nuclear medicine physician and a radiation safety officer, administers the treatment intravenously.

 

Before treatment begins, the patient receives an infusion of a non-radioactive (or cold) version of the monoclonal antibody that attaches to other areas in the body to protect them from the radioactive antibody used in the therapy. This infusion may take up to 4-5 hours to complete.  The following week, another infusion of the non-radioactive monoclonal antibody is repeated, which is then followed by a shorter infusion of the therapeutic radioactive version of the monoclonal antibody.  This infusion is much shorter and may take an hour to set up and perform.  No additional visits for infusion are needed after that.

 

What are the advantages of radioimmunotherapy?

 

RIT offers more personalized cancer treatment because radiopharmaceuticals can be tailored to the unique biologic characteristics of the patient‘s tumor, are highly selective in their ability to adhere to cancer cells, and can limit radiation exposure to healthy tissue.

 

As a result, RIT has fewer and less severe side effects and is generally well tolerated. Typical side effects are short-term and include fever, chills, reduced blood cell counts, low blood pressure, diarrhea and rash. Occasionally, secondary side effects from low blood cell counts, such as infection or bleeding, can be more severe, although these are more rare, and usually managed even when they do occur.  The two-week total treatment period for RIT is also much shorter than other cancer treatments, which can include daily radiation therapy for six weeks and four to six courses of chemotherapy administered over three or four weeks.

 

By contrast, chemotherapy and radiation therapy are non-targeted therapies that can kill both cancer cells and normal, healthy cells.  These may be often accompanied by side effects including nausea, vomiting, hair loss, diminished white blood cell and platelet counts, and a loss of energy.  Although some of these symptoms are also present with RIT, they tend to be less severe.

 

Studies have shown that patients with resistant or refractory B-cell non-Hodgkin lymphoma treated with RIT benefit from a prolonged remission.

 

Is radioimmunotherapy safe?

 

All therapies, including RIT, have side effects and risks, and RIT should only be used for specific situations. You should discuss with your medical provider the risks and benefits of RIT and any other therapies you are considering, and who will help you determine whether RIT is right for you, given your medical history. Please tell your provider about any prior therapies you have received, as this can play a role in determining the best therapy and dosage.

 

Home care

 

The medical facility where the RIT treatment is performed will provide you with instructions for special care to be taken at home, including important steps to take immediately afterwards, and in the days and week following treatment.  These instructions can vary between different facilities, and you should refer to the treating facility to give you more details.

 

Generally, one can return to work right after treatment, unless otherwise specified by the treating facility.  There may be additional medications that may need to be adjusted or stopped temporarily prior to and after treatment, such as blood thinners, and this will be instructed by your medical provider.

 

Special Considerations:

 

Body Fluid Precautions

 

In general, small amounts of the radionuclide can remain in the body following treatment. For patients treated with Zevalin , the Y-90 is primarily eliminated from the body through the urine.  Therefore, you may be instructed to make sure that any body fluid, especially urine or feces, do not come in contact with other people or your pets.  Wash hands thoroughly after bathroom use and keep the toilet thoroughly clean.  These precautions may last for a short time, generally anywhere from a day up to a week, depending upon your individual circumstance.

 

Breastfeeding Mothers

 

You must stop breastfeeding before you can be treated, but can resume it once instructed to do so; however, it is possible you may not be able to breastfeed your child anymore; you should discuss this with your provider before deciding on this type of therapy. You may safely breastfeed babies you have in the future.

 

Pregnancy

 

RIT treatment should not be given during a known pregnancy. Tell your doctor if you are pregnant or could be pregnant, or are planning to make your partner pregnant. If you are planning to become or make your partner pregnant, ask your doctor how long you should wait after treatment. You may be advised to delay the pregnancy for at least 6 to 12 months, since the ovaries and testes may be exposed to radiation during treatment.

 

Immediately following treatment, it is recommended to avoid sexual activity for up to a week, or to at least use a condom to minimize exposure of radiation to your partner.  There should be an avoidance of exchange of or contact with body fluid (urine, saliva, blood and stool) during that time period.  Subsequently, you may want to consider using contraceptives to avoid pregnancy.

 

Radiation Detection

 

Radiation detection security devices may be sensitive to the radiation levels present in patients who have recently had RIT. Ask your doctor for advice if you plan to be near radiation monitors at airports, border crossings, government buildings, hospitals, waste disposal sites, or other secure areas.  If you cannot avoid these areas, your physician can provide you with a letter describing your medical treatment. This letter of explanation should include your name, contact information for the testing facility, the name of the procedure, the date of treatment and 24-hour contact information.

 

Discarded items that are heavily stained with urine, sweat or blood may trigger alarms at waste disposal sites.  Ask your doctor for advice on how to safely dispose of these items.

 

*This information meets the requirements of the U.S. Nuclear Regulatory Commission for giving printed instructions to patients following treatment with radioiodine. Your doctor may provide additional or different printed instructions in your case, which you should follow.

 

https://www.snmmi.org/AboutSNMMI/Content.aspx?ItemNumber=29736