Cervical Cancer Symptoms and Treatment

Cervical cancer is a cancer that arises after the cells of cervical tissue become malignant. The cervix is the part where the outlet of the uterus, a female reproductive organ, joins the vagina.

Cervical cancer develops slowly over time. In almost 99% of cases, the underlying cause is a virus called human papillomavirus, abbreviated as HPV . Regular follow-up after women become sexually active is therefore important for early diagnosis. In recent years, the cervical cancer vaccine (HPV vaccine), developed against this virus, has entered routine use in many countries. We hope that vaccine awareness and vaccination will increase rapidly worldwide and that we will encounter this cancer type less and less in the future.

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Today, despite early screening and extensive awareness campaigns, only 46% of patients are diagnosed at an early stage. Across all patients, 5-year survival in cervical cancer is 67%. If it is detected at an early stage, meaning it has not extended to surrounding tissues at diagnosis and there is no metastasis to other organs, 5-year survival, or in other words, rates of recovery from the disease, exceed 90%. This demonstrates how important screening methods and early diagnosis are in cervical cancer.

Cervical Cancer Stages

The most important factor in determining cervical cancer treatment is the extent of spread, meaning its stage. It is therefore extremely important to know the extent of tumor spread, or stage, in patients diagnosed with cervical cancer.

While explaining the staging levels of cervical cancer, we also wanted to share a brief overview of treatment options that may be suitable in this section.

Stage 1 Cervical Cancer

The cancer is confined to the cervix. We call this stage a very early stage and, except in special situations, it is the most suitable stage for cervical cancer surgery . Stage IA cervical cancer is still microscopic in size; this stage can only be detected during screening.

In stage IB, cervical cancer has reached a visibly detectable size but is smaller than 4 cm and has not extended beyond the anatomical structure of the cervix.

Stage 2 Cervical Cancer

Although this is also an early stage, it is no longer a very early stage. Surgery is a treatment option for only a very small number of patients who have reached this stage. At this stage of cervical cancer, radiotherapy with concurrent chemotherapy is the main treatment option. It is therefore important for patients and their families to understand this stage, and for physicians to distinguish it using optimally performed examinations and imaging methods.

In stage IIA, the cancer is larger than 4cm but has not spread to surrounding tissues. Surgery can be performed only in this selected group of patients within the second stage.

In stage IIB cervical cancer, the tumor has extended beyond the anatomical structures of the cervix into the fat and connective tissue called the parametrium. This stage is important because surgery is no longer an option at this point in cervical cancer.

Stage 3 Cervical Cancer

The tumor has extended beyond cervical tissue, reached the lower vagina and, in some cases, blocked the kidney tubes, causing swelling of the kidney. In addition, cervical cancer is often observed to metastasize to nearby lymph nodes in the lower abdomen. The preferred treatment at this stage of cervical cancer is radiotherapy with concurrent chemotherapy; surgery is unsuitable.

Stage 4 Cervical Cancer

At this stage, complete recovery from the disease is usually not possible. Shrinking cervical cancer that has spread through the body and bringing the disease under control are the main treatment goals. We can classify this stage into two subgroups.

In stage IVA, the disease has not spread to distant organs but involves neighboring organs such as the bladder and bowel. It has therefore spread extensively within the region. In selected patients, radiotherapy with concurrent chemotherapy may be appropriate if comprehensive investigations have been performed and the tumor has not spread beyond the lower abdomen.

In stage IVB cervical cancer, there is spread to the liver, lungs, bones, brain and/or upper abdomen and lymph nodes within the chest. At this stage, a smart drug (targeted therapy) given concurrently with chemotherapy is the most suitable option.

Cervical Cancer Treatment

If cervical cancer is diagnosed at a very early stage, surgery may be prioritized; if it is not very early but remains at an early stage, radiotherapy together with chemotherapy may be prioritized. If the disease has spread to distant organs, chemotherapy and a targeted smart drug are given. Treatment selection is determined by the patient's characteristics, the cancer type and the extent of spread.

Treatment of Early-Stage Cervical Cancer

• The most commonly used treatment for early-stage cervical cancer is surgery. The surgical method used is radical hysterectomy (removal of the cervix, uterus and surrounding tissue together with lymph nodes). Removal of the lymph nodes is necessary to determine whether additional treatment will be needed at the next stage. As summarized in our cervical cancer staging section, surgery is preferred only at very early stages.

• If cervical cancer is detected at a microscopic level (stage IA), cervical conization may be performed, a method in which part of the cervical canal is removed. The most important advantage of this method is the ability to preserve fertility. Because the uterus and ovaries are preserved in this type of surgery, the patient does not lose fertility. However, this method is not preferred at more advanced stages.
• Another operation that preserves fertility is radical trachelectomy . This method involves removing all or part of the cervical canal, together with the uterus and the connective tissue called the parametrium surrounding the cervical canal. During this operation, samples are also taken from lymph nodes within the abdomen and examined. It is checked whether the cancer has spread to these areas. The uterus and ovaries are preserved in this operation.
• In cervical cancer patients who are not suitable for these surgical methods, other cervical cancer surgery methods will be planned according to the cancer stage.
• If the uterus is removed entirely or radiotherapy is applied in early-stage cervical cancer, the possibility of fertility will be eliminated.
• Even if cervical cancer is at a very early stage, radiotherapy alone may be preferred if the patient does not want surgery or is found unsuitable for surgery.
• In other situations, if cervical cancer has progressed locally but has not spread to distant organs, radiotherapy is given with concurrent chemotherapy.

Radiotherapy in Cervical Cancer Treatment

Radiotherapy is a treatment method that uses high-energy X-rays to prevent cancer cell growth and cause cancer cell death. Broadly, there are two forms of administration. The first radiotherapy method used in cervical cancer treatment is external radiotherapy , delivered from outside the body. This method uses different radiotherapy technologies and devices without disrupting the body's integrity or touching the body in any way. The other method is internal radiotherapy, called brachytherapy . In this method, radiotherapy is delivered through a device placed inside the vagina. This procedure is suitable for early-stage cervical cancer. It can also be added after completion of radiotherapy delivered externally in locally advanced cancer.

External Beam Radiotherapy (EBRT) in Cervical Cancer

Radiotherapy techniques and technology have advanced considerably today. With these techniques, called conformal radiotherapy, we minimize side effects by delivering a high dose to the tumor area and as little radiation as possible to normal tissues. In this method, advanced imaging methods such as CT and MRI are used to perform 3-dimensional radiotherapy . Radiation oncologists and physicists separately calculate and adjust the radiation doses the tumor and neighboring normal tissues will receive. The method frequently applied is intensity-modulated 3-dimensional radiotherapy. It is called intensity-modulated radiotherapy, IMRT (Intensity modulated RT=IMRT). Because radiotherapy is the main treatment for locally advanced cervical cancer, it must be remembered that, in addition to the technological capabilities of the treatment center, a skilled and experienced radiation oncologist, radiation physicist and technician in this field are important.

Stereotactic Radiotherapy (SBRT, Radiosurgery, SRS) in Cervical Cancer Treatment

These advanced radiotherapy techniques are more often preferred for recurrent tumors of limited size in a limited area. They deliver the planned tumor-destroying radiation dose through special devices in one or a few sessions (fractions).

The method known as stereotactic radiosurgery, abbreviated SRS, is performed using True-Beam, Elektra Versa and Cyber Knife , specialized and extremely expensive devices. It may be used for brain metastases of cervical cancer and/or lung, liver, bone and soft tissue metastases in a limited area if the disease is not widespread. The expertise of the center and team is extremely important in selecting and applying these methods.

Chemotherapy in Cervical Cancer Treatment

Chemotherapy is a cancer treatment method using drugs that damage cancer cells. Chemotherapy drugs act by stopping cancer cell growth and preventing their multiplication or growth. Depending on the type of chemotherapy, our normal cells may sometimes be affected as well as cancer cells. This is described as chemotherapy side effects. Today, chemotherapy side effects have been reduced almost to a minimum through many drugs developed under the heading of supportive treatments. Chemotherapy is no longer a nightmare for our patients. Nausea and vomiting, hair loss and even low blood counts can be prevented with appropriate treatments.

Chemotherapy is not needed at the very early stages of cervical cancer. Patients at these stages undergo surgery or receive radiotherapy if unsuitable for surgery. However, if the disease has progressed locally, meaning the tumor has extended beyond the cervix outward (into the parametrium) or spread to regional lymph nodes, chemotherapy is given concurrently with radiotherapy. Chemotherapy has two goals at this stage. The first is to increase the power of radiotherapy by creating synergy with it; the other is to aim for a cure by affecting both tumor cells in the cervical area and cancer cells scattered through the body that we cannot see.

In locally advanced cervical cancer, chemotherapy is administered intravenously once a week during radiotherapy. Radiotherapy is usually given for 6 weeks, and during this period, chemotherapy is given once a week until radiotherapy is completed, while treatment side effects are monitored. The chemotherapy drugs selected are cisplatin and carboplatin, called platinum drugs. These drugs cause damage by disrupting cancer cell DNA.

Stage 4 - Treatment of Metastatic Cervical Cancer

At this stage, the disease has spread through the body. Cervical cancer is frequently observed to metastasize to other organs such as the liver, lungs and bones. Except in rare situations, complete recovery from the disease is not possible. In recent years, successful results can be obtained in patients with few metastases , called oligometastatic patients. However, in patients with a large tumor burden and metastases in multiple organs, the aims of treatment are to shrink the disease, reduce the patient's symptoms and try to extend survival along with improving quality of life. Today, bevacizumab, also known as a smart drug, which has received international approval in cervical cancer, is used with chemotherapy in an effort to increase the chance of success.

Chemotherapies That May Be Preferred in Metastatic, Advanced Cervical Cancer

In newly diagnosed stage four cervical cancer that has spread through the body (metastatic), the triple treatment of cisplatin-paclitaxel-bevacizumab is administered if the patient's general condition permits combination treatment. A clinical study of the triple treatment regimen used in advanced cervical cancer showed disease regression in 50% of patients and a duration of disease control of around 17 months. During use of these drugs, preferred as the first option, some patients will show no response or disease progression after a certain period. For these patients, appropriate chemotherapy drugs from the table below are selected and administered. For patients who are unsuitable for chemotherapy initially, or unsuitable for new chemotherapy after receiving various chemotherapy regimens, treatments called supportive treatments that improve quality of life and reduce pain are preferred. Their aim is to improve quality of life rather than extend survival.

Targeted Therapies – Smart Drugs in Metastatic, Advanced Cervical Cancer

Treatments that are specific to cancer cells and do not harm normal cells are called targeted therapies, or in other words, smart drugs.

Cancer cell growth pathways are called targets, and drugs that block these pathways are called targeted therapies. One of the active pathways in cervical cancer cells is the vascular growth factor (VEGF) pathway, which causes blood vessel formation to increase the cancer's nourishment. Cancer cells need nutrients and oxygen in the blood to grow. The tumor uses VEGF receptors to form blood vessels and generate growth signals. Drugs developed against the surface receptor to which VEGF binds disrupt cancer blood vessel formation and prevent growth. Their use, often with platinum- and taxane-type chemotherapy regimens, increases the success rate in cervical cancer treatment.

Bevacizumab (brand name (Altuzan): By binding to VEGF, it prevents growth signals from being sent. Its use with chemotherapy has been shown to be effective in metastatic cervical cancer.

It is administered intravenously. The first administration takes 90 minutes, and subsequent doses take 30 minutes. It is used with chemotherapy. It is given every three weeks.

The most common side effects are increased blood pressure, diarrhea and fatigue. It may cause protein leakage in the urine. Rare but serious side effects include heart attack, stroke, bowel perforation and bleeding in the body.

Immunotherapy in Cervical Cancer Treatment

Immunotherapy drugs, regarded as the discovery of the century, eliminate our defense cells' (T cells') blindness to cancer. By activating the immune system against cancer, they thus help it destroy the cancer. These drugs have entered clinical use after demonstrating efficacy in many cancer types such as lung cancer, malignant melanoma, renal cell kidney cancer and bladder cancer.

In cervical cancer patients who have received multiple lines of chemotherapy, the rate of benefit from the chemotherapies given is below 14%. The time until disease progression is between 2-4 months. In addition, treatment-related side effects in these patients limit the effective use of drugs. Although adding the targeted treatment bevacizumab to chemotherapy provides a contribution, the success of immunotherapy has raised the question of whether it might also work in cervical cancer. Two studies seeking an answer were presented at the American Cancer Congress ASCO 2017.

The first study included 19 cervical cancer patients with recurrent disease or disease that had spread through the body. Nivolumab (brand name Opdivo) was given at 240 mg every two weeks until disease progression or a side effect developed. PD-L1 positivity was 42%. The rate of benefit from treatment was 26%, while the disease control rate was 68%. Time until disease progression was 5.5 months. The 6-month survival rate was observed to be 87%.

As well as treatment efficacy, our patients' ability to tolerate the drug and the absence of side effects are very important to us. Severe side effects related to nivolumab were observed in only 3 patients (diarrhea and liver damage). The manageability of these side effects in the study patients demonstrated that nivolumab was a safe drug.

The second study included patients diagnosed with metastatic cervical cancer who had previously received chemotherapy. A total of 47 patients entered this phase II study. Pembrolizumab (brand name Keytruda) was given intravenously at 200 mg every three weeks until disease progression. At the end of the study, the treatment response rate was 17%.

These striking results of immunotherapy agents in cervical cancer are promising for our patients and us as physicians. We will closely follow the ongoing phase III studies following these trials, and the studies evaluating use with chemotherapy, for you.

The History of Cervical Cancer

The description of cervical cancer dates back to Hippocrates' notes in the 400s. Hippocrates regarded cervical cancer as “incurable.”

In 1842, an Italian doctor, Domenico Rigoni-Stern, published his patients as a study concerning cancer-related deaths in women, showing that cervical cancer in particular was more common among married women than among women who were not sexually active.

In 1908, an Austrian obstetrician and gynecologist identified precancerous lesions of the uterine cervix, demonstrating that this cancer was preventable. Beginning with studies in 1928, the

screening test finalized in 1941, pap smear , entered use. Samples taken from the cervix were examined through the pap smear test. In 1960, it was shown that the appearances in these samples were due to viral infection. Following these studies, in 1976, German scientist Dr. Hausen detected HPV DNA in cervical cancer, identifying the causative infection, and received the Nobel Prize for this work.

In 2006, the first vaccine developed against HPV infection entered use after approval by the US Food and Drug Administration, FDA .

Understanding that human papillomavirus infection causes cervical cancer, together with the contributions of pap smear screening, enables early diagnosis. If HPV infection can be prevented by increasing vaccination, the occurrence of cervical cancer will be reduced by 90%.

What Should a Patient with Cervical Cancer Ask Their Doctor?

Would Receiving the HPV Vaccine Now Benefit Me?

The most suitable age for preventive HPV vaccination is between 9-11 years. Today, although its protection decreases at older ages, the HPV vaccine can be administered until becoming sexually active. In a person diagnosed with cervical cancer, receiving the HPV vaccine will not contribute to recovery from the existing cancer. HPV vaccination after recovery from cervical cancer may provide protection against other HPV strains, but there is currently no scientific evidence supporting this recommendation.

Can I Have Children After Cervical Cancer Treatment?

The treatment method selected will vary according to your disease stage. If surgery is suitable in early-stage disease, fertility is unaffected by conization or radical trachelectomy, whereas the possibility of fertility is lost with other operations in which the uterus and ovary are removed entirely and with external beam radiotherapy.

With advancing technology, embryo freezing before surgery and oocyte (egg) storage methods may offer the chance of having a child again after treatment when the uterus is preserved. If this is very important to you, it would be appropriate to decide with your doctor by assessing your disease stage and suitable treatment methods together.

What Should I Watch for After Cervical Cancer Surgery?

• Sexual intercourse and swimming should be avoided for the first 4-6 weeks after surgery.
• Vaginal bleeding after surgery is expected. However, if bleeding is very heavy (more than one pad per hour) or lasts longer than a week, you must contact your doctor.

What Side Effects Can Develop from Cervical Cancer Radiotherapy?

During treatment, fatigue, frequent urination, a frequent need to pass stool and abdominal discomfort may occur. These symptoms generally subside after radiotherapy ends.

Rarely after treatment, leakage of urine or stool from the vagina, pain or bleeding when passing stool, vaginal narrowing or sores with resulting pain during sexual intercourse, weakening of the pelvic bones and menopause may occur.

Will My Sexual Life Be Affected After Cervical Cancer Treatment, and What Should I Do?

Cervical cancer treatment may cause shortening and narrowing of the vaginal canal and vaginal dryness. In menstruating women, menopause may develop due to radiotherapy and chemotherapy. These physical changes may consequently cause difficulty with sexual intercourse, reduced sexual desire and difficulty reaching orgasm.

Using vaginal moisturizers and lubricants may relieve these symptoms.

If radiotherapy is planned, using vaginal dilators more than once a week during and after radiotherapy will prevent vaginal shortening and narrowing.

How Will I Be Followed After Cervical Cancer Treatments End?

A doctor's examination should be performed every 3-4 months during the first two years. Between years 3-5, an examination every 6 months is sufficient, and after 5 years, once a year.

A sample should be taken annually from the birth canal (pap smear test)

Your doctor will plan blood tests, ultrasound or other imaging methods according to your symptoms and examination findings.