CLINICAL TREATMENT PROTOCOLS OF

BREAST CANCER

PHL 425

Dr. Mohamed M. sayed-Ahmed

BREAST CANCER

Breast cancer (BC) is the most common cancer and one of the leading causes of cancer-related death worldwide. About 1.2 million women worldwide are diagnosed with breast cancer (BC) every year.

According to the most recent National Cancer Registry (NCR) in Saudi Arabia, BC is at the top and the most frequent tumour among all the malignancies seen in Saudi females, accounting 26 %.

In Saudi Arabia, BC that developed before the age 40 accounted for 28 % of all female breast cancers compared with only 6.5% in USA.

Considering the growth and aging of population in Saudi Arabia, future burden of BC in Saudi Arabia is expected to increase by approximately 350 % by the year 2025 which could demonstrate enormous demands on health care resources. For all these reasons, BC represents a local and complex health problem in kingdom of Saudi Arabia.

Factors That Increase Risk of Breast Cancer

•Family History

•Lifestyle

•Personal History

Family History

If your mother, sister, or daughter has developed breast cancer before menopause, you are three times more likely to develop the disease.

If two or more close relatives (e.g., cousins, aunts, grandmothers) have/had breast cancer, you are at increased risk as well.

Recently, scientists have found that mutations in genes BRCA1 and BRCA2 increase one's susceptibility to breast cancer. A simple blood test can tell you if you have such a condition.

Personal HistoryIf you've had breast cancer, you have an

increased risk of getting it again. Also, if you've had benign breast disease (e.g., fibrocystic breast disease), you are at an increased risk.

The following also put you at greater risk:

• If you began menstruating early (before age 12)

• If you take birth control pills (though evidence

is not conclusive)

Life Style

• Several studies found a lower incidence of breast cancer among women who exercise regularly.

• Higher proportion of breast cancer among obese women.

• There is increased risk of breast cancer with increased alcohol use (i.e., 3 or more drinks per week); perhaps due to the fact that alcohol increases blood estrogen levels.

Additional Risk Factors

• If you never have children

• If you have children when you are 30 or older

• If you have menopause at 55 or older

• If you take Hormone Replacement Therapy (HRT)

• Higher estrogen levels are strongly linked with susceptibility to breast cancer.

Trouble Signs That Should Not Be Ignored

1. Finding a lump, hard knot or thickening

2. Unusual swelling, warmth, redness or darkening

3. Change in size or shape of your breast

4. Finding an itchy, scaly sore or rash on the nipple

5. Pulling in of the nipple or other parts of the breast

6. Nipple discharge that starts suddenly

7. Pain in one spot that does not vary with cycle

• BREAST CANCER arises in the milk-producing glands of the breast tissue. Ductal carcinoma begins in the ducts, and lobular carcinoma has a pattern involving the lobules or glands.

• Risk factors for the development of breast cancer, includes:

• family history of breast cancer in mother or sister (families in which there is a high breast cancer frequency have mutations affecting the tumor suppressor genes BRCA-1 and BRCA-2.

• early onset of menstruation and late menopause

• reproductive history: women who had no children or have children after age 30 and women who have never breastfed have increased risk

• history of abnormal breast biopsies

• hormone replacement therapy (HRT) that provides significant relief of menopausal symptoms, prevention of osteoporosis, and possibly protection from cardiovascular disease and stroke

DIAGNOSIS OF BREAST CANCER A- When a patient has no signs or symptoms:

• Screening involves the evaluation of women who have no symptoms or signs of a breast problem

• 1- Breast self examinations: • It is recommended that women get into the habit of doing monthly breast

self examinations to detect any lump at an early stage.

• 2- Mammography:

• Mammography is the study of the breast using x ray. The actual test is called a mammogram. There are two types of mammograms.

• A- A screening mammogram is ordered for women who have no problems with their breasts. It consists of two x-ray views of each breast.

• B- A diagnostic mammogram is for evaluation of new abnormalities or of patients with a past abnormality requiring follow-up (i.e. a woman with breast cancer treated with lumpectomy). Additional x rays from other angles or special views of certain areas are taken.

A mammogram of a normal breast

A mammogram showing an abnormal growth. A biopsy is needed to confirm whether this is indeed cancer.

B- When a patient has physical signs or symptoms:

such as the presence of a lump within the breast. Skin dimpling, nipple retraction, or bloody nipple discharge.

• 1- BIOPSY: Depending on the situation, different types of biopsy may be performed. The types include incisional and excisional, (complete removal) biopsies. In an incisional biopsy, the physician takes a sample of tissue, and in excisional biopsy, the mass is removed.

• 2- FINE NEEDLE ASPIRATION BIOPSY: In a fine needle

aspiration biopsy, a fine-gauge needle may be passed into the lesion and cells from the area suctioned into the needle can be quickly prepared for microscopic evaluation (cytology).

• 3- CORE NEEDLE BIOPSY:

• 4- Computed tomography: (CT scan, CAT scans), and magnetic resonance imaging (MRI) have only a very occasional use in the evaluation of breast lesions.

CLINICAL STAGING OF BREAST CANCER

Stage 1: Tumour is 2 cm and no cancer cells are found in the lymph nodes.

Stage 2: Tumour is between 2 to 5 cm, and the cancer has spread to the lymph nodes

Stage 3A: Tumor is larger than 5 cm and has spread to the lymph nodes, which have grown into each other.

Stage 3B: Tumour has spread to tissues near the breast, (local invasion), or to lymph nodes inside the chest wall, along the breastbone.

Stage 4: Tumour has spread to skin and lymph nodes beyond the axilla or to other organs of the body.

TREATMENT PROTOCOLS OF BREAST CANCER

Types of Treatment: Local and Systemic

Local Treatment: SurgeryRadiation Therapy

Systemic Treatment:Chemotherapy

Hormone TherapyBiological Therapy

CLINICAL TREATMENT PROTOCOLS OF BREAST CANCER

SURGERY

• Radical Mastectomy: surgical removal of the entire breast and axillary contents along with the muscles down to the chest wall.

• Modified Radical Mastectomy: Surgical removal of the entire breast and axillary contents, but the muscles of the chest wall are not.

• Lumpectomy: If the tumor is less than 4 cm (1.5 in) in size and located so that it can be removed without destroying a reasonable cosmetic appearance of the residual breast, just the primary tumor and a rim of normal tissue will be removed.

RADIOTHERAPY

• Like surgical therapy, radiation therapy is a local modality—it treats the tissue exposed to it and not the rest of the body. Radiation is usually given post-operatively after surgical wounds have healed. The pathologic stage of the primary tumor is now known and this aids in treatment planning.

Side effects of radiation therapy:

1- reddening of the skin 2- muscle stiffness 3- mild swelling 4- tenderness in the area 5- long term shrinking of the irradiated breast

MammoSite 5-Day Targeted Radiation Therapy

• MammoSite Targeted Radiation Therapy works from the inside, meaning that a higher daily dose can be used for a shorter period of time – 5 days vs. 5-7 weeks for traditional external beam radiation therapy.

* The MammoSite® Radiation Therapy System received FDA clearance in 2002.

Advantages of MammoSite:1- Treatment with MammoSite 5-Day Targeted Radiation Therapy can help you get back to your normal life sooner – just 5 days vs. 5-7 weeks for traditional external beam radiation therapy.

2- MammoSite places the radiation source inside the lumpectomy cavity (the space left when a tumor is removed). This delivers radiation to the area where cancer is most likely to recur.

3- This therapy is given on an outpatient basis and No hospital stay is required.

MammoSite 5-Day Targeted Radiation Therapy

Balloon and lumpectomy

Chemotherapy

CMF

cyclophosphamide 600 mg/m2 PO d1-14

Methotrexate (MTX) 40 mg/m2 IV d1+8

5-Fluorouracil (5-FU) 600 mg/m2 IV d1+8

To be repeated every 4 weeks for 6 cycles

Modified CMF

Cyclophosphamide 600 mg/m2 IV d1

Methotrexate (MTX) 40 mg/m2 IV d1

5-Fluorouracil (5-FU) 600 mg/m2 IVd1

To be repeated every 3 weeks for 6 cycles

CAF

Cyclophosphamide 600 mg/m2 IV d1

Doxorubicin 60 mg/m2 IV d1

5-Fluorouracil (5-FU) 600 mg/m2 IVd1+8

To be repeated every 4 weeks ( 4 cycles adjuvant)

AC

Doxorubicin 60 mg/m2 IV d1

cyclophosphamide 600 mg/m2 IV d1+8

to be repeated every 3 weeks (4 cycles)

Doxorubicin + Paclitaxel

Doxorubicin 50 mg/m2 IV d1

Paclitaxel 220 mg/m2 IV d2

• To be repeated every 3 weeks (with G-CSF support).

• The total dose of doxorubicin should not exceed 450 mg/m2 to avoid the cardiotoxicity.

Modified AC: AC followed by Paclitaxel

Doxorubicin 60 mg/m2 IV d1

cyclophosphamide 600 mg/m2 IV d1+8

• to be repeated every 3 weeks (4 cycles), then

• Paclitaxel 175 mg/m2 IV(3h inf)d1

CEF

Cyclophosphamide 100 mg/m2 PO d1-14

Epirubicin 60 mg/m2 IV d1+8

5-Fluorouracil (5-FU) 500 mg/m2 IVd1+8

• To be repeated every 4 weeks for 6 cycles

Predictive Markers In Breast Cancer

Among the first clinically utilized predictive markers in BC are:

* ER/PR tailoring response to antihormonal therapy .

* HER-2 gene amplification and protein overexpression. The monoclonal antibody trastuzumab is selectively used in the treatment of BC in patient who displays HER-2 positivity

Hormonal Therapy of Breast Cancer

• Patients with estrogen receptor positive tumors will typically receive a hormonal treatment after chemotherapy is completed. Typical hormonal treatments include:

A- ANTI-ESTROGEN

• It has been documented that one-third of all breast carcinomas are ESTROGEN-DEPENDENT and will regress after ESTROGEN DEPRIVATION. Thus reducing the level of estrogen remains a valuable target for treatment of breast carcinoma in both premenopausal and postmenopausal women. Reducing the effect of estrogen can be mediated by:

1- Agents that block Estrogen at receptor level: TAMOXIFEN

2- Agents that inhibit estrogen biosynthesis: AROMATASE INHIBITORS.

1- TAMOXIFEN (Nolvadex): (20 mg/d , PO, 5 years)

• As adjuvant therapy for patient with estrogen receptor positive irrespective of age and nodal status. As palliative therapy for postmenopausal patients with estrogen receptor positive advanced/metastatic tumours. Also, for the prevention of breast cancer in high risk women.

• TAMOXIFEN is an antineoplastic nonsteroidal selective estrogen receptor modulator (SERM). Tamoxifen competitively inhibits the binding of estradiol to estrogen receptors, thereby preventing the receptor from binding to the estrogen-response element on DNA. The result is a reduction in DNA synthesis and cellular response to estrogen. In addition, tamoxifen up-regulates the production of transforming growth factor B (TGFb), a factor that inhibits tumor cell growth, and down-regulates insulin-like growth factor 1 (IGF-1), a factor that stimulates breast cancer cell growth.

2 -AROMATASE INHIBITORS

• Aromatase inhibitors (AIs) act through

inhibition of the cytochrome P450,

AROMATASE, which catalyses the

conversion of androgen substrates to

estrogen, which are the main source of

estrogen in postmenopausal women.

1- ANASTROZOLE (Arimidex)

• A nonsteroidal inhibitor of estrogen synthesis that resembles paclitaxel in chemical structure.

• As a third-generation aromatase inhibitor, anastrozole selectively binds to and reversibly inhibits aromatase, a cytochrome P-450 enzyme complex found in many tissues including those of the premenopausal ovary, liver, and breast; aromatase catalyzes the aromatization of androstenedione and testosterone into estrone and estradiol, the final step in estrogen biosynthesis. In estrogen-dependent breast cancers, anastrozole may inhibit tumor growth.

2- LETROZOLE (Femara)

• A nonsteroidal inhibitor of estrogen synthesis that resembles paclitaxel in chemical structure.

• As a third-generation aromatase inhibitor, letrozole selectively and reversibly inhibits aromatase, a cytochrome P-450 enzyme complex found in many tissues including those of the premenopausal ovary, liver, and breast.

• Aromatase catalyzes the aromatization of androstenedione and testosterone into estrone and estradiol, the final step in estrogen biosynthesis.

• In estrogen-dependent breast cancers, anastrozole may inhibit tumor growth.

3- Exemestane (Aromasin)

• A synthetic androgen analogue. Exemestane binds irreversibly to

and inhibits the enzyme aromatase, thereby blocking the conversion

of cholesterol to pregnenolone and the peripheral aromatization of

androgenic precursors into estrogens.

CLINICAL PHARMACOLOGY OF THE NEW GENERATION OF AROMATASE INHIBITORS

CharacteristicsAnastrozole(Arimidex)

Letrozole(Femara)

Exemestane(Aromasin)

NatureNon-steroidalNon-steroidalsteroidal

Class of AIsType II, reversibleType II, reversibleType I, irreversible

Daily clinical dose

(mg/day)

12.525

Total monthly dose

(mg)

3075750

Time to steady-state

plasma levels (days)

7607

Half-life (hrs)417227

Time to maximal

Estradiol suppression

(days)

3-42-37

Intratumoural activity

reported

YESYESYES

FDA approvalYESYESYES

•B- Lutenizing hormone-releasing hormone (LHRH) agonists:

1- Leuprolide acetate

2 -Goserelin

Immunotherapy

TRASTUZUMAB (Herceptin)

TRASTUZUMAB is a recombinant humanized monoclonal

antibody directed against the human epidermal growth factor

receptor 2 (HER2).

After binding to HER2 on the tumor cell surface, trastuzumab induces an antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2.

HER2 is overexpressed by many adenocarcinomas, particularly breast adenocarcinomas

• This therapy requires the obligation of HER-2 tumour typing following any surgical intervention of an invasive breast cancer.

• Trastuzumab must only be administered to female HER-2-positive patients, i.e., in whom the tumours overexpress the HER-2 protein or amplify the HER-2 gene.

• Monitoring of HER-2 in tumours is essential:

• The overexpression of HER-2 must be searched for using immunohistochemisty (IHC) in embedded tumour fragments, or using genic amplification in situ hybridisation (FISH1 or CISH2 technique).

Triple Negative Breast Cancer

* TNBC is a subtype of BC that lacks the expression of:

- Estrogen receptor (ER)

- Progesterone receptor (PR)

- Human epidermal growth factor receptor (HER-2).

* This uncommon subtype approximately representing 15 % of all BC cases with poor prognosis despite responding to conventional chemotherapy regimens

Characteristics of TNBC

1- Aggressive and early patterns of metastases.

2- Unique molecular characteristics.

3- BRCA-1 and BRCA-2 mutations.

4- Poor prognosis.

5- lack of targeted therapeutics.

Obstacles in Treatment of TNBC

1- ER and HER-2 are not expressed in TNBC.

2- As a result, therapies that decrease estrogen synthesis or block ER or HER-2 including aromatase inhibitors, estrogen receptor blockers, and trastuzumab are ineffective in its treatment.

* Poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme, plays an important role in the repair of single-strand DNA breaks via the base excision repair pathway.

* PARP-1 represents an important novel target in cancer therapy.

Poly(ADP-ribose) polymerase (PARP-1) and TNBC

Earlier and recent studies confirmed that loss of BRCA-dependent DNA repair mechanisms combined with the PARP inhibitor, olaparib is associated with synthetic lethality and augmented cell death.

Preliminary results of a recent randomized phase II trial of chemotherapy (carboplatin plus gemcitabine) combined with the PARP inhibitor, in metastatic TNBC, showed significantly improved clinical benefit rate, progression free survival and overall survival compared with carboplatin plus gemcitabine alone.

PARP-1 Inhibitors and TNBC

Data from phase II study with the PARP inhibitor, olaparib, as a single agent to treat sporadic TNBC showed a limited and unimpressive result which further supports the use of combination PARP inhibitor plus chemotherapy in the treatment of patients with sporadic TNBC.

Results from a randomized, double-blind, multicenter study which investigated the efficacy of olaparib in combination with paclitaxel in the first or second line treatment of metastatic TNBC, yielded notable toxicity patterns in the form of grade 2 to 4 neutropenia which required dose modifications for both olaparib and paclitaxel.

PARP-1 Inhibitors and TNBC

In 2012, Patel et al., compared the actions of the PARP inhibitor, iniparib, with the more extensively characterized PARP inhibitors, olaparib and veliparib, and reported that iniparib failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel and its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.

PARP-1 Inhibitors and TNBC

PHL 417

Dr. Mohamed M. Sayed-Ahmed

TARGETED AND BIOLOGICAL

THERAPY OF CANCER

1 -Monoclonal Antibody Drugs For Cancer Treatment

What is a monoclonal antibody:

A monoclonal antibody is a laboratory-produced molecule that's carefully engineered to attach to specific defects in your cancer cells. Monoclonal antibodies mimic the antibodies your body naturally produces as part of your immune system's response to germs, vaccines and other invaders.

How do monoclonal antibody drugs work

1- Make the cancer cell more visible to the immune system. The immune system attacks foreign invaders in your body, but it doesn't always recognize cancer cells as enemies. A monoclonal antibody can be directed to attach to certain parts of a cancer cell. In this way, the antibody marks the cancer cell and makes it easier for the immune system to find.

The monoclonal antibody drug Rituximab attaches to a specific protein (CD20) found only on B cells, one type of white blood cell. Certain types of lymphomas arise from these same B cells. When Rituximab attaches to this protein on the B cells, it makes the cells more visible to the immune system, which can then attack. Rituximab lowers the number of B cells, including your healthy B cells, but your body produces new healthy B cells to replace these. The cancerous B cells are less likely to recur.

RITUXIMAB (Rituxan)

• A recombinant chimeric murine/human antibody directed against the CD20 antigen, a hydrophobic transmembrane protein located on normal pre-B and mature B lymphocytes.

• Following binding, rituximab triggers a host cytotoxic immune response against CD20-positive cells.

• Rituximab is used in the treatment of B-cell Non-Hodgkin's lymphomas.

• MECHANISM OF ACTION:

• Complement fixation• ADCC• Direct cytotoxicity via apoptotic pathway activated by binding

to CD20.

Alemtuzumab (al-em-to-zoo-mab) (MabCampath®)

Alemtuzumab is humanized monoclonal antibody that targets CD52, a glycoprotein highly expressed on both B-CLL cells and normal B and T cells.

Therefore, CLL seemed the optimal setting for this new agent, as it is primarily a malignancy of the peripheral blood and bonemarrow. Alemtuzumab (Campath-1H) was approved by the FDA for the treatment of B-cell CLL unsuccessfully treated by alkylating agents and fludarabine.

The mechanism of action of alemtuzumab is not well understood, but it is presumed to workvia ADCC, CDC, and/or apoptosis.

Alemtuzumab-How is it given

MabCampath is given as a drip (infusion) through a fine tube (cannula) inserted into a vein in arm or back of the hand. Each drip takes approximately two hours. It can also be given as an injection under the skin (subcutaneously).

Some people have an allergic reaction to MabCampath. To reduce the risk of a reaction the first few doses are given slowly. You may also be given some antihistamines, paracetamol and sometimes a small dose of steroids before the infusion. These will help to reduce the risk of reactions. If you do have a reaction, the infusion can be stopped and started again once the symptoms are over.

You will be asked to stay in hospital for a few hours after the infusion, or possibly overnight, to be monitored. The dose of MabCampath is increased over a few days until the recommended dose is achieved. This usually takes three to seven days and is known as dose escalation. Once the recommended dose is achieved the treatment is given three times a week (e.g. on Monday, Wednesday and Friday). Most people have treatment for 4–12 weeks.

2- Block growth signals:

Chemicals called growth factors attach to receptors on the surface of normal cells and cancer cells, signaling the cells to grow. Certain cancer cells make extra copies of the growth factor receptor. This makes them grow faster than the normal cells.

Monoclonal antibodies can block these receptors and prevent the growth signal from getting through.

Cetuximab

Cetuximab (Erbitux), a monoclonal antibody approved to treat colon cancer and head and neck cancers, attaches to Epidermal Growth Factor Receptors (EGFR) on cancer cells that accept a certain growth signal (EGF).

Cancer cells and some healthy cells rely on this signal to tell them to divide and multiply. Blocking this signal from reaching its target on the cancer cells may slow or stop the cancer from growing.

How Cetuximab WorksCetuximab attaches itself to the EGFRs and prevents the receptors from being activated. This stops the cells from dividing. It therefore has the potential to stop the cancer cells from growing. It works in a different way from both chemotherapy and hormonal therapy.

Cetuximab may also make the cancer cells more sensitive to chemotherapy.

Tests may be done to find the level of EGFR in the body before cetuximab is given. This can help the doctors to know whether you are likely to benefit from this treatment. Testing can be done at the same time as diagnosis of the cancer, or samples of cancer cells from previous biopsies or surgery may be used.

Cetuximab is given by a drip into the vein (intravenously) through a fine tube (cannula) inserted into a vein. The first dose is given slowly, usually over two hours. After this, doses are given weekly and this normally takes about an hour. The first dose is usually larger than the weekly maintenance treatments. You may be given other medicines before cetuximab to lessen the side effects during treatment.

Panitumumab (ABX-EGF)Panitumumab belongs to a subgroup of monoclonal antibodies, known as epidermal growth factor receptor (EGFR) inhibitors.

Epidermal growth factor (EGF) is a protein that is present in the body. There are receptors for EGF on the surface of many types of cancer cell. When EGF binds to these receptors, chemical signals are triggered which cause the cells to grow and reproduce.

Panitumumab attaches itself to the EGFR, and prevents it from being activated. This stops the internal chemical signalling, and inhibits the growth of cancer cells that have the EGFR on their surface.

Tests may be done to check the level of EGFR present in the tumour; these will tell if you are likely to benefit from panitumumab. Testing can be done at the same time as diagnosis, or samples of cancer cells from previous biopsies, or surgery, may be used.

TRASTUZUMAB (Herceptin)

TRASTUZUMAB is a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2).

After binding to HER2 on the tumor cell surface, trastuzumab induces an antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells that overexpress HER2.

HER2 is overexpressed by many adenocarcinomas,

particularly breast adenocarcinomas.

This therapy requires the obligation of HER-2 tumour typing following any surgical intervention of an invasive breast cancer.

The activity of trastuzumab is directed against the human epidermalgrowth factor receptor-2 (HER-2). Herceptin® must only be administered to female HER-2-positivepatients, i.e., in whom the tumours overexpress the HER-2 protein

oramplify the HER-2 gene.

Monitoring of HER-2 in tumours is essential: The overexpression of

HER-2 must be searched for using immunohistochemisty (IHC) in

embedded tumour fragments, or using genic amplification in situ

hybridisation (FISH1 or CISH2 technique). IHC, the search for genic

amplification must be positive to be able to envisage such

3- Stop new blood vessels from forming:

Cancer cells rely on blood vessels to bring them the oxygen and nutrients they need to grow. To attract blood vessels, cancer cells send out growth signals. Monoclonal antibodies that block these growth signals may help prevent a tumor from developing a blood supply, so that it remains small. Or in the case of a tumor with an already-established network of blood vessels, blocking the growth signals could cause the blood vessels to die and the tumor to shrink.

The monoclonal antibody bevacizumab (Avastin) targets a growth signal called vascular endothelial growth factor (VEGF) that cancer cells send out to attract new blood vessels.

BEVACIZUMAB (Avastin)

• A recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine.

• Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels.

4- Deliver radiation to cancer cells:

By combining a radioactive particle with a monoclonal antibody, doctors can deliver radiation directly to the cancer cells. This way, most of the surrounding healthy cells aren't damaged.

Radiation-linked monoclonal antibodies deliver a low level of radiation over a longer period of time, which researchers believe is as effective as the more conventional high-dose external beam radiation.

90Y-Ibritumomab (Zevalin)(90Y) Yttrium-90 (it-ree-um).

90Y-Ibritumomab (Zevalin), approved for non-Hodgkin's lymphoma, combines a monoclonal antibody with radioactive particles.

The ibritumomab monoclonal antibody attaches to receptors on cancerous blood cells and delivers the radiation. Yttrium-90 produces radiation that is strong enough to destroy cancer cells. It can also affect normal cells.

A number of monoclonal antibody drugs are available to treat various types of cancer. Clinical trials are studying monoclonal antibody drugs in treating nearly every type of cancer

How zevalin works and givenAs Zevalin enters the bloodstream, the monoclonal antibody portion recognises and attaches to the CD20 protein. Energy is then released from the yttrium radioisotope, damaging or killing the B-cell. Zevalin attacks both normal and abnormal (malignant) B-cell lymphocytes. However, the body quickly replaces any normal white blood cells that are damaged, so the risk of side effects from this is very small.

Zevalin is used with Rituximab. Together they lock onto a protein called CD20, which is found on the surface of one of the main types of normal white blood cells (B-cell lymphocytes). CD20 is also present on the surface of most of the abnormal B-cell lymphocytes, which occur in many types of non-Hodgkin lymphoma. The monoclonal antibodies attack both normal and abnormal (malignant) B-cell lymphocytes.

Zevalin is given as a single 'one-off' treatment and not as repeated courses of treatment.

It consists of two components, given approximately one week apart: Retuximab and Zevalin

Rituximab is given on the first day of treatment to reduce the number of normal healthy B-cells. This prevents the Zevalin from attaching to and destroying healthy, non-cancerous cells. Rituximab is given as a drip into a vein (intravenous infusion). It is given slowly over a few hours. You will be given some steroids and antihistamines beforehand to reduce the risk of an allergic reaction.

You will receive a second infusion of rituximab about one week after your first dose. Within four hours of this infusion you will go to the nuclear medicine or radiotherapy department to have the Zevalin treatment. This is given by drip and takes about ten minutes.

How zevalin works and given

131I-tositumomab (toss-i-to-mo-mab), (Bexxar)

Nonmyeloablative use of an 131I anti-CD20

murine antibody, is well tolerated and highly effective in the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL (B-NHL). BEXXAR has a radioactive substance called iodine131 attached to it. The monoclonal antibody in BEXXAR, tositumomab, attaches to a protein found on the surface of the B-cells. As a result, the radioactive iodine delivers radiation directly to these cells. This destroys the lymphoma B-cells. Unfortunately it may also affect some normal cells.

Gemtuzumab (gem-to-zoo-mab)

Gemtuzumab ozogamicin (GO, Mylotarg) consists of a recombinant, humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a potent antitumor antibiotic. Within the acidic environment of lysosomes afterinternalization, calicheamicin dissociates from the antibody and migrates to the nucleus, where it binds within the minorgroove of DNA and causes double-stranded DNA breaks.

It is mainly used as part to treat some types of acute myeloid leukaemia (AML).

It carries a chemotherapy drug called ozogamicin directly to the cancer cells. As the chemotherapy is only delivered to cells showing the CD33 protein it may not affect normal cells within the body.

FDA-APPROVED MONOCLONAL ANTIBODIES TARGETS and INDICATIONS

AntibodyTrade Name Target AntigenFDA Indication

RituximabRituxanCD20B-NHL

90Y-IbritumomabZevalinCD20B-NHL

131I-tositumomabBexxarCD20B-NHL

AlemtuzumabCampathCD52CLL

Gemtuzumabozogamicin

MylotargCD33AML

CetuximabErbituxEGFRmetastaticCRC

PanitumumabABX-EGFEGFRmetastaticCRC

TrastuzumabHerceptinHER2/neuMetastaticBr CA

FDA-APPROVED MONOCLONAL ANTIBODIES

Rituximab (Rituxan) was the first mAb approved by the FDA in 1997 for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL).

Alemtuzumab (Campath-1H) was approved by the FDA for the treatment of fludarabine-refractory B-cell CLL.

Patients with metastatic Her-2 Neu overexpressing metastatic breast carcinoma can receive targeted therapy with trastuzumab (Herceptin).

Bevacizumab and cetuximab recently received FDA approval for the treatment of metastatic colorectal carcinoma.

Gemtuzumab ozogamicin (Mylotarg), an antibody-drug conjugate, was approved by the FDA in 2000 for the treatment of CD33-positive, relapsed acute myeloid leukemia (AML) patients

90Y-ibritumomab tiuxetan (Zevalin) was the first radiolabeled antibody approved for cancer therapy. Subsequently, 131I-tositumomab (Bexxar) was approved by the FDA for the treatment of relapsed or refractory low-grade follicular or transformed CD20-positive B-cell NHL.