ROLE OF CHEMOTHERAPY IN

OVARIAN CANCER

ANITA SINGH (SRF)MEDICAL ONCOLOGYIRCH, AIIMS FEB 28,2014

What is the ovarian cancer ? Ovarian cancer is any cancerous growth that may occur in different parts of

the ovary. The majority of ovarian cancers arise from the epithelium of the ovary.

According to the American Cancer Society it is the 8th most common cancer among women in the USA. In the UK ovarian cancer is the 5th most common cancer among females, after breast, bowel , lung  and uterine cancer. 

Approximately 5,500 women in the UK and 21,000 women in the USA are diagnosed with ovarian cancer each year. Worldwide, around 140,000 women die of ovarian cancer every year. 

Overall survival:75% at 1 year46% at 5 years38% at 10 years

Picture showing the O.C

Fig. - 1 Fig. - 2

Sign and symptoms:-The following are examples of possible early symptoms of ovarian cancer:

o Abdominal pain, distentiono Pain in the pelviso Back acheo Indigestion or heartburno More frequent and urgent urinationo Pain during sexual intercourseo Changes in bowel habits, such as constipation

As ovarian cancer progresses these symptoms are also possible:o Nauseao Weight losso Breathlessnesso Fatigue (tiredness)o Loss of appetite

Risk factors of ovarian cancer ?

1.     Age

2.     Nulliparity

3.     Continuous ovulation

4.     Ovulation Induction Agents : Due to over-stimulation of the ovaries increasing ovulation.

5.     Family and personal history of cancers

6.     Inherited Genetic mutation : BRACA1/BRCA2 gene mutations.

How is ovarian cancer diagnosed?

Clinical findings of Ovarian Cancer patients :

Any physical signs, an abdomen mass and ascites may be present. Pelvic examination, and lymph nodes should also be palpated if present.

Screening Tests :

Ultrasound of the ovaries and measurement of levels of a protein called CA-125 in the blood.

Imagings :

Imaging tests like CT, MRI, or ultrasound can reveal an ovarian mass, but only a sampling of the tissue (biopsy) can determine whether the mass is cancerous.

How is ovarian cancer staging determined?

Staging is the process of classifying a tumor according to the extent to which it has spread in the body at the time of diagnosis.

Ovarian cancer staging :

Stage 1 : Limited to one or both ovaries

Stage 2 : Limited to disease in the pelvis

Stage 3 : Disease outside of the pelvis, but limited to the abdomen, or lymph node involvement, but not including the inside

of the liver

Stage 4 : Disease spread to the liver or outside of the abdomen

What is the treatment for ovarian cancer ?

OVARIAN CANCER

SURGERY(laparotomy with TAH + B/L SPO +

lymph nodes + IFO + peritoneal washings and as much debulking as

possible).

ADJUVANT CHEMOTHERAPY

NEO-ADJUVANT CHEMOTHERAPY

SURGERY

CHEMOTHERAPY

Randomization

Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS

Ovarian, tubal or peritonal cancerFIGO stage IIIc-IV (n = 718)

3 x Platinum based CT 3 x Platinum based CT

≥ 3 x Platinum based CT

Primary Debulking Surgery Neoadjuvant chemotherapy

Interval debulking (not obligatory)

Interval debulking if no PD

≥ 3 x Platinum based CT

Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications

NACT + IDS versus PDS: ITT

IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953.

Median survial

PDS : 29 Months

IDS : 30 Months

What is chemotherapy ? 

Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is the treatment of  cancer with one or more cytotoxic anti-neoplastic drugs (chemotheraputic agents) as part of a standardized regimen.

It works by interfering with the ability of rapidly growing cells to divide or reproduce themselves.

Most of an adult's normal cells are not rapidly growing, they are not as affected by chemotherapy.

Exceptions to this include rapidly dividing cells such as bone marrow (where the blood cells are produced), hair, and lining of the gastrointestinal tract.

How chemotherapy kills cancer cells ?

Chemotherapy kills cells that are in the process of splitting into 2 new cells.

Cancer cells divide much more often than normal cells. So they are more likely to be killed by chemotherapy.

Some chemotherapy drugs kill dividing cells by damaging the part of the cell's control centre that makes it divide. Other drugs interrupt chemical processes involved in cell division.

Chemotherapy drugs that you have in these ways circulate all round the body in the bloodstream. They can reach cancer cells almost anywhere in the body. This is known as systemic treatment.. 

How chemotherapy kills dividing cells ?

Nucleus contains chromosomes, which are made up of genes. These genes have to be copied exactly each time a cell divides into 2 to make new cells.

Some drugs damage cells at the point of splitting. Some damage the cells while they are making copies of all their genes before they split.

You may have a combination of different chemotherapy drugs. The combination will include chemotherapy drugs that damage cells at different stages in the process of cell division. So, with more than one type of drug, there is more chance of killing more cells.

Chemotherapy affects healthy body tissues where the cells are constantly growing and dividing. The skin, bone marrow, hair follicles and lining of the digestive system are examples of cells that are constantly growing and dividing. 

Fig…

How well chemotherapy works ?

1. The chance of the chemotherapy curing your cancer depends on the type of cancer you have.

With some types of cancer most people are cured by chemotherapy. Examples of cancers where chemotherapy works very well are testicular

cancer and Hodgkin lymphoma.

2. With some cancers, chemotherapy can't cure the cancer on its own. But it can help in combination with other types of treatment.

For example, many people with breast or bowel cancer have chemotherapy after surgery to help lower the risk of the cancer coming back.

3. With some cancers, if a cure is unlikely, your doctor may still suggest chemotherapy to -

Shrink the cancer Relieve your symptoms

4. Give you a longer life by controlling the cancer or putting it into remission.

What remission means ?

It means that after treatment there is no sign of the cancer. It may be complete remission and partial remission.

Complete remission - means that the cancer or leukaemia can't be detected on scans, X-rays, or blood tests, etc. Doctors sometimes call this a complete response. 

Partial remission - means the treatment has killed some of the cells, but not all. The cancer has shrunk, but can still be seen on scans and doesn't appear to be growing. so that other treatments are more likely to help, such as surgery or radiotherapy. This is sometimes called a partial response. 

What does chemotherapy do?

Depending on your type of cancer and how advanced it is, chemotherapy can:

Cure cancer - when chemotherapy destroys cancer cells to the point that your doctor can no longer detect them in your body and they will not grow back.

Control cancer - when chemotherapy keeps cancer from spreading, slows its growth, or destroys cancer cells that have spread to other parts of your body.

Ease cancer symptoms (also called palliative care) - when chemotherapy shrinks tumors that are causing pain or pressure.

How does chemotherapy affect the body?

There are quite a few different types of chemicals used as chemotherapy. There are now more than 90 different chemotherapy drugs in use.

Most chemotherapy drugs fit into four main groups

Alkylating agents Microtubule inhibitors (vinca alkaloids and taxanes) Cytotoxic antibiotics Anti metabolites

What the drugs all have in common is that they attack and kill cells that are in the process of dividing and multiplying.

The different drugs work on cells at different stages of division.

Continued…

At any one time, there will be cells at each of the stages of cell division. So, one drug might kill cancer cells that are making new DNA just before they start to divide. And another drug may kill cells that are halfway through the dividing process.

By combining drugs, cancer doctors make sure even more cancer cells are killed.

Having  cycles of treatment also increases the cell killing power of chemotherapy.

How can we give the chemotherapy?

Chemotherapy is the use of drugs to treat cancer.

It enter the bloodstream and reaches all parts of the body.

Most of the time, systemic chemo uses drugs that are injected into a vein (IV) or given by mouth.

In IP chemotherapy it is injected through a catheter directly into the abdominal cavity.

Chemo for ovarian cancer most often is a combination of 2 or more drugs, given on every 3 to 4 weeks.

The standard approach is the combination of a platinum compound (cisplatin or carboplatin) and a taxane (paclitaxel or docetaxel). For IV chemotherapy, most doctors favor carboplatin over cisplatin.

The typical course of chemo for epithelial ovarian cancer involves 3 to 6 cycles.

If the first chemo seemed to work well and the cancer stayed away for a time, it can be treated with additional cycles of the same chemotherapy.

Chemotherapy for epithelial ovarian cancer [(PACLITAXEL (175 mg/m2) + CARBOPLTIN(AUC – 6)]

Standard Chemotherapy Regimens

For Advanced Ovarian Cancer

IV paclitaxel + IP cisplatinIV paclitaxel + IV carboplatinIV docetaxel + IV carboplatin

Side effects of chemotherapy - Chemotherapy drugs kill cancer cells but also damage some normal cells.

Common temporary side effects include:Nausea and vomitingLoss of appetiteLoss of hairHand and foot rashesMouth sores

Chemotherapy can damage the blood-producing cells of the bone marrow, so patients may have low blood cell counts. This can result in :

Increased chance of infection (caused by a shortage of white blood cells)Bleeding or bruising after minor cuts or injuries (caused by a shortage of

blood platelets)Fatigue (caused by low red blood cell counts)

DRUG BINDING WITH DNA

The different ways in which a drug molecule can interact with the DNA are:

Through control of transcription factors: Here the drug molecule doesn’t directly interact with the DNA instead it will interact with the protein that binds to the DNA molecule and hence altering the functions.

Forming DNA-RNA hybrids: By binding to RNA molecule that in turn binds to single stranded DNA forming DNA-RNA hybrids which will interfere with the transcription activity.

Direct binding of molecules: Here the small aromatic ligand molecules directly bind to the DNA double helix and these molecules are of many types like groove binders, intercalators etc.

PACLITAXEL

Paclitaxel was isolated from the bark of the Pacific yew tree 

Taxus brevifolia.  Paclitaxel is also known as Taxol and Onxol to be an anti-cancer drug. The

drug is the first line treatment for ovarian cancer. The chemical formula of paclitaxel is C47H51O14.

Mechanism of action

Paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of microtubules, and the binding of paclitaxel locks these building blocks in place.

Continue…. Fig…

CARBOPLTIN

Carboplatin binds to DNA and damages the DNA in a cell. The DNA damage caused by carboplatin results in cell death. It is an “alkylating agent”.

Inside the body carboplatin undergoes a chemical reaction with water intracellularly resulting in the generation of a positively charged aquated species that attacks nucleophilic sites on DNA.

This is the "alkylation" action of carboplatin, that hinders the growth of the tumor by stoping division of cancer cells.

Fig. - 1 Fig. - 2

cis Diammin (1, 1 cyclobutanedicarboxylato) platinum

BINDING WITH DNA:

Fig. - 1 Fig. - 2

NOTE: Carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (CBDCA) ligand in place of the two chloride ligand, which are the leaving groups in cisplatin.

Continued….

Of the DNA adducts, 25-30% are intra-strand AG diadducts, and 1-3% are crosslinks between the two strands.

Platinum crosslinks affect the positioning of the DNA around the histone octamer, forcing it into an asymmetric arrangement with respect to the core histone proteins.

This asymmetry of the DNA as it wraps around the histone octamer, would greatly affect gene damage and their subsequent repair.

The most important feature of platinum drugs from which their anticancer activity arises is their ability to elicit DNA damage.

Figure shows crosslinks formed between carboplatin with DNA and adduct formation

Ovarian cancer is any cancerous growth that may occur in different parts of the ovary.

Overall survival depends on stages and type of cancer. Histopathology report (biopsy) can determine whether the mass is cancerous or not.

Chemotherapy is the treatment of cancer with one or more cytotoxic anti drug. Chemotherapy kills cells while splitting or while making copies of their genes

before splitting. Combination of different drugs have more chances of killing more cells. Aim of chemotherapy is to tumor or try to stop cancer coming back after

surgery or radiotherapy.

SUMMARY

Thank you