Cervical cancer

Cervical cancer is a type of cancer that occurs in the cervix, the lowermost part of the uterus that connects to the vagina. This type of cancer can be prevented by PAP smear screening and a vaccine called HPV ( human papillomavirus).
A sexually transmitted infection play a role in causing most cervical cancer. The immune system of the body prevents the virus from doing harm, when exposed to HPV. However, the virus survives for years, contributing to the process that causes some cervical cells to become cancer cells.
 All women are at high risk of cervical cancer. It is the fourth most common type of cancer in women. It occurs most commonly in women over age 30. More than 15% of new cases are in women above age 65, however, especially those women who have not been getting regular screening. Therefore, a woman can reduce the risk of developing cervical cancer by having screening tests and receiving a vaccine that protects against HPV infection.

Cervix is made up of two parts and is covered with two different types of cells,

• Endocervix – it is the opening of the cervix that leads into the uterus. It is covered with the glandular cells.
• Exocervix – it is the outer part of the cervix that can be seen with the help of speculum. It is covered with squamous cells.

Transformation zone is the place where these two cell types meet in the cervix. Most cancers begin in the cells. Most cervical cancers begin in the cells in the transformation zone.

What do you mean by Pre – cancers of the cervix?  

In the transformation zone, cells do not suddenly change into cancer. Instead, the normal cells of the cervix first gradually develop abnormal changes that are called pre- cancerous. Doctor’s use several terms to describe these Precancerous changes including cervical intra epithelial neoplasia (CIN), Squamous intraepithelial lesion (SIL) and Dysplasia.

Although cervical cancer starts from cells with pre- cancerous changes, only some of the women with pre- cancers of the cervix will develop cancer. In most women, pre-cancerous cells will go away without any treatment. But, in some other cases pre-cancerous tumors turn into true invasive cancers. Pre-cancers treatment can be preventable almost in all cervical cancers.

What are the types of Cervical cancer?

The main types of cervical cancer are as follows;

• Squamous cell carcinoma – this type of cervical cancer forms in the lining of the cervix. About 80% to 90% of cervical cancers are squamous cell carcinoma. These cancers develop from cells in the exocervix. It most often begins in the transformation zone.
• Adenocarcinoma – this type of cervical cancer forms in the cells that produce mucus. About 10% to 20% of cervical cancers are adenocarcinoma. These cancers develop from glandular cells.
• Mixed carcinoma Or Adenosquamous carcinoma – this type of cervical cancers have features of both squamous cell and adenocarcinoma.

What are the early signs and symptoms of Cervical cancer?  
In the early stages of cervical cancer, a woman may experience no symptoms at all until it’s far along.As a result women should have regular cervical smear tests, or Pap tests.
A Pap test is a type of prevention. It aims not to detect cancer but to reveal any cell changes that indicate the possible development of cancer, so that a woman can take early treatment.
The cause of a symptom may also be a different medical condition that is not cancer, that’s why women need to seek medical advice if they have a new symptom that does not go away.

The most common symptoms of cervical cancer are:

• Bleeding after sexual intercourse
• Bleeding in post- menopausal women
• Discomfort during sexual intercourse
• Pelvic pain
• Vaginal discharge tinged with blood
• Vaginal discharge with a strong odour
• Unusual bleeding or vaginal discharge
• Dysuria
• Weight loss
• Loss of appetite
• Fatigue
• Joint pain

If any of these symptoms appear, it is necessary to talk with your doctor about them even if they appear to be symptoms of other or less than serious conditions. The precancerous is found and treated, the better the chance that the cancer can be prevented or cured.
What causes cervical cancer?

 Cancer is the result of the uncontrolled growth and division of abnormal cells.
Abnormal cells can have two problems as follows:

• They don’t die.
• They continue dividing.

Cervical cancer begins when healthy cells in the cervix develop changes in their DNA. A cell’s DNA contains the instructions that tell it what to do. It is not clear what causes cervical cancer but, it’s certain that HPV (Human papillomavirus) plays a role.

HPV is very common and most women with this virus never develop cancer. It is a sexually transmitted infection which spreads through sexually contact and lead to cancer.

Most people will get HPV at some point in their lives and not realise it because their bodies fight with the infection. However, if your body does not fight the infection, it can cause the cells of the cervix to change into cancerous cells.

• Early detection of HPV plays a key role in the prevention of cervical cancer.
• Regular screening can help to identify cell changes before they become cancerous cells.
• The HPV vaccine can help to prevent HPV infection by protecting a woman against the HPV, which causes up to 90% of all cervical cancers.

What are the risk factors of getting cervical cancer?
A risk factor is anything that increases the chance of getting a disease such as cancer. When you think about risk factors, it helps to focus on those you can change Or avoid like smoking or HPV rather than those you cannot, such as a woman’s age and family history.
  However, it is still important to know about risk factors that cannot be changed, because it is even more important for those who have these factors to get regular screening tests to find cervical cancer at an early stage.

There are some risks factors of cervical cancer as follows:

• Human papillomavirus (HPV) infection – it is the most important risk factor for cervical cancer. It is a group of more than 150 related viruses, these viruses can cause a type of growth called papillomas, which are known as warts.

It can infect cells on the surface of the skin and those lining the genitals, anus, mouth and throat but not affect the blood or internal organs.

It can easily spread from one person to another during skin to skin contact, through sexual activity including vaginal, anal and even oral sex.

Some types of HPV cause warts on different parts of the body, like on the hand and feet, and others tend to cause warts on the lips or tongue.

• Sexual history – The sexual history can increase the risk of cervical cancer, the risk is most likely affected by increasing the chances of exposure to HPV.

Multiple sex partners.

Someone with HPV infection or who has many sexual partners.

At young age below 18, becoming sexually active.

• Smoking – when someone smokes they and those around them are exposed to many cancer-causing chemicals that affect organs other than the lungs.

Women who smoke are about twice as

likely as those who don’t smoke get cervical cancer. Smoking also makes the immune system less effective in fighting HPV infections.

• Weak immune system – HIV the virus that causes AIDS, weakens the immune system and puts people at higher risk of HPV infection.

A woman may be more likely to develop cervical cancer if her immune system is weakened by another health condition and may have HPV.
Some women who are at risk for cervical cancer are those taking drugs to suppress their immune response, such as those being treated for an autoimmune disease, ( in which the body’s immune system attacks and destroys healthy body tissue by mistake) or those who have had an organ transplant.

• Chlamydia infection – it is a relatively common kind of bacteria that can infect the reproductive system. It is spread by sexual contact women who are infected with chlamydia infection often have no symptoms but can cause pelvic inflammation, leading to infertility.

Certain studies show that the chlamydia bacteria may help HPV grow and live on in the cervix which may increase the risk of cervical cancer.

• Long term use of birth control pills –

Women who are taking birth control pills or oral contraceptives for a long time increase the risk of cervical cancer.
Research states that the  cervical cancer risk goes up the longer a woman takes birth control but the risk goes back down again after the oral contraceptives are stopped, and returns to normal after many years of stopping.

• Multiple full term pregnancies – women who have had 3 or more full – term pregnancies have an increased risk of developing cervical cancer.

It is due to the increased exposure to HPV infection with sexual activity. Researchers have also pointed to hormonal changes during pregnancy as possibly marking women more susceptible to cancer growth or HPV infection.

• Family History – Cervical cancer may run in some families. If a woman’s mother or sister had cervical cancer, her chances of getting the disease are higher than if nobody in the family had a history.
• Economic status – a woman from poor economic status doesn’t have easy access to adequate health care facilities, including HPV tests, Pap tests with cervical cancer screening. Therefore they may not get screened or treated for pre- cervical cancer.
• Diethylstilbestrol – it is a hormonal drug that was given to some women between 1938 to 1971 to prevent miscarriage. There is about 1 case of vaginal or cervical clear – cell adenocarcinoma in every 1,000 women, whose mother’s took diethylstilbestrol during their pregnancy.

Daughters of the mother’s who had diethylstilbestrol may be at increased risk of developing squamous cell cancers and pre- cancers of the cervix linked to HPV.

Is there any factor that may lower the risk of cervical cancer?

Intrauterine devices (IUDs) – researchers suggest that women who had used an IUDs had a lower risk of getting cervical cancer.

Low risk effect was seen even in women who had an IUDs for less than a year and the protective effect remained after the IUDs were removed. IUDs do have some risks. Therefore, a woman with multiple sexual partners should use condoms to lower her risk of getting sexually transmitted infections no matter what other form of contraception she uses.

Can we prevent cervical cancer?

There are two most important things which a woman can do to prevent cervical cancer is

• to get the HPV vaccine if she is eligible
• to be tested regularly

Cervical cancer starts with Pre-cancerous changes, the first way of prevention is to find and treat pre- cancer before it becomes invasive cancers and second is to prevent Pre-cervical cancer.

How can we find cervical pre-cancers?

The best way to prevent cervical cancer is to have screening tests. With the help of screening we can find out the pre-cancerous cells before they can turn into invasive cancers.

• Pap test Or Pap smear and HPV tests are specific rests used during screening to detect cervical cancer.

It is a test used to collect cells from the cervix to find cancer and pre-cancers.

• HPV vaccine – these vaccines only work to prevent HPV infection, they will not treat an infection that is already there. Therefore, to be most effective, the HPV vaccine should be given before a person becomes exposed to HPV infection.

HPV vaccine helps to prevent pre-cancers and cancers of the cervix. These types of vaccines are also approved to help prevent other types of cancers and anal and genital warts.

There are some side effects of HPV vaccines that are usually mild. The most common are:

• Short – term redness
• Swelling
• Soreness at the injection site

It is important to know that no vaccine provides complete protection against all cancer causing types. So, routine cervical cancer screening is still needed.

• To limit the exposure to HPV – HPV can be spread during skin to skin contact – including vaginal, anal or oral sex.

This means that the virus can be spread without sex, even possible for w genital infection to spread through hand to genital contact.

HPV infection can be able to spread from one part of the body to another, this may start in the cervix and then spread to the vagina and vulva.

• Limit the number of sex partners- avoid sec with people who have had many other sex partners may lower the risk of exposure to HPV infections.
• Use protection while having sex – condoms provide protection against HPV but they don’t completely prevent infections. But, still condoms provide some protection against HPV, and they also helps to protect against HIV and some other sexually transmitted diseases.
• Stop smoking – quitting smoking is another important way to reduce the risk of cervical pre-cancers and cancers.

How can we diagnose cervical cancer?

There are many tests used for diagnosing cervical cancer, the following tests can be used to diagnose which are as follows,

• Medical history and physical examination – it includes information related to risk factors and symptoms of cervical cancer.
• Pap smear – it is a part of a woman’s regular pelvic examination, in this test the samples are taken from inside and outside of the cervix.
• Human papillomavirus (HPV) – this test is similar to a pap smear test, the test is done on a sample of cells from the cervix. Many people have HPV but don’t have cervical cancer, so HPV testing alone is not enough for a diagnosis of cervical cancer.

Several types of biopsies can be used to diagnose cervical pre- cancers and cancers, if the biopsy can completely remove all of the abnormal tissue, it might be the only treatment needed.

• Colposcopic biopsy – In this type of biopsy, the cervix is examined with a colposcope to find the abnormal areas. This procedure may cause mild cramping, brief pain and some slight bleeding after the procedure.
• Endocervical curettage – If colposcopy does not show any abnormal areas, another method must be used to check that area for cervical cancer.

In this procedure, a curettage Or brush is used to scrape the inside of the canal to remove some of the tissue, which is then sent for the lab.

• Cone biopsy – this type of biopsy is also known as “Conization”, in this biopsy the doctor removes a cone – shaped piece of tissue from the cervix, the tissue removed in the cone includes the transformation zone where cervical pre- cancers and cancers are most likely to start.
• Cystoscopy – A slender tube with a lens and a light is placed into the bladder through the urethra.
• Proctoscope – it is a visual inspection of the rectum through a lighted tube to look for spread of cervical cancer into the rectum.

Imaging studies

There are some tests that can show if and where the cancer has spread, which will help in the treatment plan.

• Chest x-ray – this may be done to see if cancer has spread to the lungs.
• CT scan – it is usually done if the tumor is larger in size or if there is concern about the spread of the cancer.
• MRI – this test looks at the soft tissue parts of the body better than other Imaging tests.
• PET CT – this test can help to see if the cancer has spread to lymph nodes. This test can also be useful if the doctor thinks the cancer has spread but doesn’t know where.
• Intravenous Urography – it is also known as intravenous pyelogram, it is an x-ray of the urinary system taken after a special dye which is injected directly into a vein. This test can find abnormal areas in the urinary tracy, caused by the spread of cervical cancer.

How many stages of cervical cancer are there?

 The FIGO (International federation of gynecology and obstetrics) staging system is used most often for cancer of the female reproductive organs, including cervical cancer.

There are total 4 stages are there in cervical cancer which are as follows,

STAGE 1

The cancer is limited and found only in the cervix, it has not spread to distant sites and it is small in size. This stage is further separated into subcategories.

• Stage 1A : the cancer is still so small that a microscope can see it.
• Stage 1A1: There is a tiny amount of cancer. The tumor has grown 3mm Or less into the tissue of the cervix.
• Stage 1A2: The tumor has grown 3 to 5 mm into the tissue of the cervix.
• Stage 1B: though bigger than a stage 1A tumor, the cancer remains contained in the cervical tissue.
• Stage 1B1: The tumor is 2cm Or less in size has grown 5mm Or more into the cervix’s tissue.
• Stage 1B2: The tumor measures between 2 and 4cm.
• Stage 1B3: The tumor is at least 4cm.

STAGE 2

The cancer has spread to the upper part of the vagina  or the tissue surrounding the uterus, but it has not spread to lymph nodes or distant sites.

• Stage 2A: The cancer has spread to the upper part of the vagina but has not reached the tissue surrounding the uterus.
• Stage 2A1: The tumor measures 4 cm or smaller in size.
• Stage 2A2: The tumor measures 4cm or larger in size.
• Stage 2B: The cancer has spread to the tissue surrounding the uterus.

STAGE 3

The cancer has reached the lower portion of the vagina and/or the muscles that surround the pelvic area ( pelvic walls). The tumor may be large enough to cause kidney problems by blocking the tubes that transport urine from the kidneys to the bladder. It may have reached nearby lymph nodes.

• Stage 3A: The cancer has entered the lower portion of the vagina, but it has not reached the pelvic walls.
• Stage 3B: The cancer has reached the pelvic walls and or it is causing kidney problems by blocking one or both ureters.
• Stage 3C: The cancer has grown itnto lymph nodes.
• Stage 3C1: The cancer has grown into lymph nodes in the pelvis.
• Stage 3C2: The cancer has reached lymph nodes around the aorta.

STAGE 4

The cancer had spread into the bladder, rectum, or beyond the pelvic are to distant parts of the body.

• Stage 4A: The cancer has grown into nearby organs such as the bladder or rectum, or is spreading out of the pelvic area.
• Stage 4B: The cancer has spread to organs such as the liver, lungs, bones or distant lymph nodes.

Recurrent

Recurrent cancer is the type of cancer that has come back after the treatment. Cervical cancer can come back either in the pelvis where it began or spread to other areas throughout the body, such as the lungs, lymph nodes, and bones. If the cancer does return, there will be another round of tests to learn about the extent of the recurrence. The goal of treatment is to eliminate all of the cancer, but sometimes cancer cells go undetected, or new cancer cells develop. As a result, cancer can potentially return to the cervix or the surrounding area, or to another part of the body.

What is the best treatment for cervical cancer?
The treatment of cervical cancer depends on several factors, including the type and stage of cancer, possible side effects, and the preferences of the patient and overall health.
Take time to learn about all of the treatment options and be sure to ask questions and clear the doubts. These types of talks are called “shared decision- making”.
Shared decision- making is when a patient and doctor work together to choose treatments that fot the goals of the care. It is particularly important for cervical cancer because there are different treatment options.
The different types of treatments used for cervical cancer are described below.
Surgery
Many women with cervical cancer will have some type of surgery, which helps to

• Diagnose cervical cancer
• Determine how far the cancer has spread
• Treat the cancer especially for early- stage cancers

Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. For cancer that has not spread beyond the cervix, these procedures are often used:

• Conization: The use of the same procedure as a cone biopsy to remove all the abnormal tissue. It can be used to remove cervical cancer that can only be seen with a microscope, called microinvasive cancer.
• Loop electrosurgical excision procedure (LEEP) : The use of an electrical current passed through a thin wire hook. The hook removes the tissue. It can be used to remove microinvasive cervical cancer.
• Hysterectomy: The renoval of the uterus and cervix. A hysterectomy can be simple or radical.

A simple hysterectomy is the removal of the uterus and cervix

A redical hysterectomy is the removal of the uterus, cervix, upper vagina, and the tissue around the cervix. A redical hysterectomy also includes an extensive pelvic lymph node dissection, which means lymph nodes are removed this procedure can be done using a large cut in the abdomen, called laprotomy, or using smaller cuts, called laparoscopy.

• Bilateral salpingo – oophorectocy: If needed, this surgery is the removal of both fallopian tubes and both ovaries. It is done at the same time as a hysterectomy.
• Redical trachelectomy: A surgical procedure in which the cervix is removed, but the uterus is left intact.

It includes pelvic lymph bode dissection.

This surgery may be used for young patients who want to preserve their fertility. This procedure had become an acceptable alternative to a hysterectomy for some patients.

• Exenteration: The removal of the uterus, vagina, lower colon, rectum or bladder if cervical cancer has spread to these after radiation therapy. This type of surgery is rarely recommended. It is most often used when cancer has come back after the radiation therapy.

Side effects and complications: 

Side effects or complications after surgery vary depending on the type and extent of the procedure. Sometimes, patients experience,

• Bleeding
• Infection
• Damage to the urinary or intestinal system
• Affect sexual health

Radiation therapy

Radiation therapy is the use of high energy  x-rays or other particles to destroy cancer cells. This type of therapy may be given alone, before surgery or instead of surgery or after the surgery to shrink the tumor. Radiation therapy may be used as:

• Main part of the treatment, for some stages of cervical cancer, the preferred treatment is radiation alone or surgery followed by radiation.

For other stages, radiation and chemotherapy are given together known as concurrent chemoradiation, and it is the preferred treatment as the chemotherapy helps the radiation work better.

• Treat cervical cancer that has spread or that has come back after treatment.

Radiation therapy may be used to treat cervical cancer that has spread to other tissues and organs.

The types of radiation therapy most often used to treat cervical cancer are;

• External beam radiation therapy

• Brachytherapy 

The most common type of radiation therapy is called external- beam radiation therapy, which is given from a machine outside of the body.
When radiation therapy is given using implants, it is called brachyrherapy or internal radiation therapy.
A radiation therapy regimen, usually consists of a specific number of treatments given over a set period of time that combines external and internal radiation therapy. This combined approach is the most effective treatment to reduce the chances the cancer will come back, called a recurrence.
Common side effects of radiation therapy;

• fatigue
• Mild skin reactions
• Nausea and vomiting
• Diarrhea
• Skin changes, mild redness , peeling
• Menstrual changes
• Low blood counts
• Vaginal pain

Long term side effects of radiation therapy

• Vaginal stenosis- The scar tissue can make the vagina narrower called vaginal stenosis, less able to stretch, or even shorter, which can cause pain while having sex.
• Vaginal dryness
• Rectal bleeding or rectal stenosis
• Urinary problems
• Weakened bones

Medical therapy 
Medication may be given through the bloodstream to reach cancer cells, throughout the body. This type of treatment is generally prescribed by a medical oncologist, a doctor who is specialized in treating cancer with medication.
There are following types of medication used for cervical cancer,
Chemotherapy – This therapy includes the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells.

• These drugs enter the bloodstream and can reach almost all areas of the body, making this treatment useful for killing cancer cells in most part of body.

A chemotherapy regimen usually consists of a specific number of cycles given over a set period of time. In the treatment, one drug at a time or a combination of different drugs may be given at the same time. In cervical cancer treatment, chemotherapy is often given in combination with radiation therapy.
How is chemotherapy given?

• Chemotherapy can be given orally, all the drugs used to treat cervical cancer are given Intravenously. Sometimes, a slightly larger and sturdier intravenous is required to give chemo. These are known as central venous catheters (CVP)
• Chemo is given in cycles, followed by a rest period to give you time to recover from the effects of the drugs.

Chemotherapy as a part of the treatment for cervical cancer
For some stages of cervical cancer, the preferred treatment is chemotherapy and radiation given together called concurrent chemoradiation.
The chemotherapy helps the radiation work better, options for concurrent chemoradiation includes,

• Cisplatin given weekly during radiation. This drug is given Intravenously before the start of radiation therapy treatment.
• Cisplatin plus 5-fluorouracil (5-FU) given every 3 weeks during the radiation therapy.

The chemo drugs most often used to treat cervical cancer that has come back or spread to other areas include,

• Cisplatin
• Carboplatin
• Paclitaxel (taxol)
• Topotecan

Common side effects of chemotherapy:

• Nausea and vomiting
• Hair loss
• Loss of appetite
• Diarrhea

These side effects usually go away after treatment is finished.

Rare side effects:

• Hearing loss
• Kidney damage
• Peripheral neuropathy

(Numbness, pain, tingling in the hands or feet)
Targeted therapy
Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival.
This type of treatment blocks the spread and growth of cancer cells and limits the damage to the healthy cells in the body.
Some targeted therapy drugs, for example, monoclonal antibodies work in more than one way to control cancer cells and may also be considered immunotherapy, because they boost the immune system.
Different types of targeted therapy can be used to treat cervical cancer.

Targeting drugs in blood vessel formation

• Vascular endothelial growth factor (VEGF) is a protein that helps tumors to form new blood vessels, known as angiogenesis, to get nutrients they need to grow.

Some targeted drugs called angiogenesis inhibitors stop vascular endothelial growth factors from working and block this new blood vessel growth.

• Bevacizumab or Avastin is an angiogenesis inhibitor that can be used to treat advanced cervical cancer.

It is a monoclonal antibody , which is a man-made version of a specific immune system protein that targets VEGF.
This drug is often used with chemotherapy for a time. Then, if the cancer responds, the chemotherapy may be stopped and the bevacizumab given by itself until the cancer starts growing again.
Side effects of drugs that target VEGF

• High blood pressure
• Nausea
• Lethargy
• Blood clots
• Wound healing
• Heart failure
• Bleeding

Antibody-drug conjugates is a monoclonal antibody linked to a chemotherapy drug.
Tisotumab vedotin – tfrv ( Tivdak)

• This antibody- drug conjugates has an antibody that targets tissue- factor (TF) protein on cancer cells.
• It acts like a homing signal by attaching to the TF protein bringing the chemotherapy directly to the cancer cells.
• It can be used to treat cervical cancer that has metastasized to another part of the body or come back after initial treatment, typically after at least 2 other drug treatments have been tried.
• This type of drug is usually given Intravenously.

Side effects of tisotumab vedotin- tftv

• Nausea
• Hair loss
• Vomiting
• Bleeding
• Diarrhea
• Rash
• Peripheral neuropathy

Some major side effects

• Dry eye
• Vision loss
• Changes in vision
• Corneal ulceration

Immunotherapy for cervical cancer
Immunotherapy is the use of medicines to boost a person’s own immune system to recognize and destroy cancer cells more effectively.

• Immunotherapy typically works on specific proteins involved in the immune system to enhance the immune response.
• They can sometimes be used to treat cervical cancer.
• They are different and sometimes have less severe side effects than chemotherapy.
• Some immunotherapy drugs, like monoclonal antibodies, work in more than one way to control cancer cells and may also be considered targeted therapy, because they block a specific protein on the cancer cells to keep it from growing.

Immune checkpoint inhibitors

• An important part of the immune system is its ability to keep itself from attacking the body’s normal cells.

To do this, it uses “checkpoints” proteins on immune cells that need to be turned on or off to start an immune response.

• Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system.

Pembrolizumab or Keytruda targets DP 1, a protein on immune system cells called T cells that normally helps to keep these cells from attacking other cells in the body. By blocking PD-1, these drugs boost the immune response against cancer cells.

Before pembrolizumab can be used, a lab test might need to be done on cancer cells to show they have at least a certain amount of the PD-L1 protein.

If enough PD -L1 protein is detected, pembrolizumab can be used as,

• For cervical cancer that has come back or that has spread while getting chemotherapy or may be after chemotherapy.
• A first treatment, along with chemotherapy, with or without bevacizumab, for cervical cancer that is not shrinking with current treatment, has come back, or has spread to distant sites.
• This immunotherapy drug is given as an intravenous infusion every 3 or 6 weeks.

Side effects of immunotherapy

• Fever
• Headache
• Nausea
• Loss of appetite
• Joint pain
• Diarrhea