Dose-dense CA - Cyclophosphamide and Doxorubicin for breast cancer treatment

CA or AC is the name of this treatment regimen, which is used in breast cancer and is conventionally administered every 21 days. However, in young patients with a good general condition whose tumor is locally advanced, it can also be administered every 14 days before or after surgery. Giving more intensive chemotherapy by administering it every fourteen days, that is, more frequently, is called dose-dense ( dose dense ) chemotherapy. The medical oncologist decides how frequently this chemotherapy regimen will be given. CA is one of the most widely used chemotherapy regimens with proven effectiveness in breast cancer treatment. The red drug is another name associated with this treatment regimen. Its most prominent feature is its hair-loss effect. It used to be known as one of the feared chemotherapy regimens with the strongest nausea-inducing effect, but it has lost this frightening reputation, particularly since the development of the anti-nausea medicine containing the active ingredient aprepitant and its introduction into our patients' treatment.

Agents included in the CA chemotherapy regimen

Each drug in the CA protocol is designed to destroy cancer cells or slow their growth (you can find the drugs' detailed mechanisms of action at the end of the article).

C: Cyclophosphamide ( Cyclophosphamide )

A: Doxorubicin ( the most widely known trade name is Adriamycin )

DD-ACis another abbreviation referring to this chemotherapy regimen.

Purpose of treatment

Dose-dense CA can be used before surgery to reduce tumor size ( neoadjuvant ) and after surgery ( adjuvant ) to destroy cancer cells that may remain in the body.

Administration method, dose and schedule

• Doxorubicin 60mg/m2 is administered intravenously (İntraVenöz = İ.V.) on day 1 over 5-15 minutes, in what we call a push administration.
• Cyclophosphamide 600 mg/m2 is administered slowly on day 1 over 30-60 minutes. This administration of a drug through a vein over a specified period is called an infusion in medical terminology.

Drug administration times can be changed as the physician considers appropriate.

Total estimated duration of cyclophosphamide and Adriamycin infusion

• The CA protocol takes approximately 90 minutes.
• Administration times have been determined based on clinical trials. However, this duration may vary according to the doctor's recommendation or how well the patient tolerates treatment.

The supportive fluids given to prepare for treatment, known as premedication, can increase this duration.

Dose-dense CA is generally administered in outpatient chemotherapy units, where patients return home after treatment.

Dose-dense CA is repeated every 14 days. Each period is called 1 cycle of treatment. Each cycle can be repeated up to four times depending on the stage of the disease. Treatment may last two or three months, depending on the response to treatment, the patient's tolerance and the recommended number of cycles.

Side effects

In multidrug regimens, each drug has its own side effects. The side effects that may occur when these two drugs are given together have been estimated from clinical trial results. The most common side effects associated with dose-dense CA in clinical trials are as follows:

• A decrease in white blood cells ( leukopenia and neutropenia ) (9%)
• Pain (9%)
• Nausea (6%) 
• Vomiting (6%) 
• Muscle/joint pain (5%) 
• Infection (3%) 
• Mouth sores (3%) 
• Diarrhea (1%) 
• Hair loss ( hair preservation if not used, %100 )

Note: Although the rate of neutropenic fever associated with dose-dense CA has not been reported in clinical trials, it is common if medicines to prevent neutropenic fever are not used (more than 20%). Neutropenic feverrefers to febrile opportunistic infections that can occur when the number of neutrophils, a type of white blood cell, falls below a critical level ( generally 500 / mm3 ).

Follow-up

How frequently is follow-up necessary?

Blood tests need to be checked before each chemotherapy cycle. The required blood tests are a complete blood count ( hemogram ) and a comprehensive metabolic panel ( biochemistry ). Other blood tests may be added according to the physician's recommendation.

How frequently is imaging ( radiological examination ) necessary?

If CA chemotherapy is given after surgery for preventive purposes ( adjuvant ), imaging is not performed during treatment except in special circumstances. If breast cancer is locally advanced and treatment is given to shrink the tumor before surgery and improve the success of surgery ( neoadjuvant treatment ), the imaging method performed before treatment ( USG, eMaR, PET-BT ) is repeated after 4 cycles to determine whether the tumor has regressed. In metastatic, that is, stage 4. breast cancer, imaging methods should be checked before treatment starts and at certain intervals after treatment. Magnetic Resonance Imaging ( MRG ), Computed Tomography ( BT ) or Positron Emission Tomography ( PET ) are among the imaging methods used.

How do blood test or imaging results affect treatment?

Depending on the results, your doctor may continue dose-dense CA as planned, change its dose or change the treatment.

Points to consider

• Drinking more fluids is recommended, particularly on the days cyclophosphamide is given ( an extra maximum of 1-2 liters per day is sufficient ). Drinking plenty of fluids helps flush and frequently empty your bladder, reducing the bladder side effects of a substance called acrolein which is a waste product of cyclophosphamide. Adequate fluid intake also helps reduce nausea and vomiting.
• After Dose-Dense CA, an injection of a blood cell growth factor ( such as filgrastim, lenograstim or pegfilgastrim ) is generally necessary.
• Your oncology pharmacist should check whether the drugs interact with one another.

Individual drug label information

Doxorubicin

• Mechanism of action: The main mechanism of action of doxorubicin as a chemotherapy drug is to prevent DNA replication by interacting directly with DNA and blocking its copying. It does this by stabilizing the DNA strand that opens for replication, thereby preventing the DNA double helix from closing again.
• It is red in color.
• It can affect heart function. Therefore, cardiac ultrasound ( echocardiography = EKO ) should be performed before the first chemotherapy is given and every 3 months if treatment will continue for a long time.
• The dose should be adjusted for patients with reduced liver function.
• In a small number of people, it has been associated with the development of secondary cancers (a probability over 10 years of %1.5).
• It is available under names such as Adrimisin, Doxo-Teva, Doxorubicin Fresenius, Doxorubicin Kocak and Doxtu.

General side effects of doxorubicin

• Nausea, vomiting, diarrhea and mouth sores
• Leakage of the drug outside the vein during administration can cause skin irritation, and this condition is called extravasation in medical terminology.
• It turns urine orange. This is temporary.
• Temporary hair loss
• Infections may occur due to a decrease in white blood cells ( neutropenia ).

Cyclophosphamide

• Mechanism of action: The component responsible for the main tumor-shrinking effect of cyclophosphamide is phosphoramide mustard. This component is active only in cells with low levels of the enzyme aldehyde dehydrogenase. Phosphoramide mustard causes irreversible cross-links in DNA and leads the cell into programmed death ( apoptosis ). Cyclophosphamide is one of the most successful and widely used cancer drugs. Moreover, it is also a powerful immune-system-suppressing ( immunosuppressive ) agent and the most widely used drug in blood and marrow transplantation.
• It can cause infertility. If couples want to have children, measures should be taken to preserve fertility. 
• The dose needs to be reduced in patients undergoing dialysis.
• It has been associated with the development of secondary cancers in a small number of people.
• It is available under the names Endoksan and Syklofosfamid.

General side effects of cyclophosphamide

• A low white blood cell count, increasing the risk of opportunistic infections.
• Nausea or vomiting; these may have an acute onset ( first 24 hours ) or be delayed ( between days 2 - 5. ).
• Temporary hair loss