Cancer Therapies

[Connie B]

An easy-to-understand explanation of the various types of cancer treatment

As scientists learn more about cancer’s biology and how it affects each patient, better methods have become available to treat cancer and prevent recurrence. This overview will discuss the types of therapy you may receive, including some new ones that have become available only during the past few years.

Surgery

Surgical removal of solid tumors is almost always necessary, and may require complete removal of the affected organ. Less invasive and less extensive methods are available in some cases, including laparoscopic surgery or lumpectomy as opposed to mastectomy (removing tumor tissue and a margin of surrounding benign tissue compared with removing the entire breast).

Laparoscopic surgery is performed through one or more small incisions that allow a thin fiberoptic scope, called a laparoscope, and specially designed surgical instruments to be inserted into the abdomen to remove the tumor. If the procedure is done in the chest wall, it’s called a thoracoscopy. Disease-free survival and recurrence rates for many types of cancer are about the same when compared with traditional open surgery, and hospital recovery time may be significantly shorter.

Radiofrequency ablation, or RFA, has emerged as a promising therapy for patients unable to undergo surgical resection or who have not responded to other therapies. This outpatient procedure uses localized heat to destroy tumor cells, and can be used in combination with chemotherapy and radiation therapy. Cryoablation is a similar procedure that uses rapid freezing and thawing to kill the cancer cells.

Chemotherapy

Several types of chemotherapy, each with its own mechanism of action and side effects, are available for cancer. Many new drugs have greater efficacy and less toxicity than first-generation chemotherapy from 50 years ago. But much of the improvement in efficacy and toxicity is greater knowledge about how to deliver these drugs, including optimal dose and frequency of dose, alone and in combination.

Chemotherapy is used in several ways. It can be given as the primary—or main—treatment for some cancers, such as lymphoma and leukemia. Oncologists have also discovered chemotherapy given after surgery, known as adjuvant therapy, can often dramatically improve survival and delay disease progression. Neoadjuvant chemotherapy is given before surgery, and often shrinks tumors enough to permit less extensive operations. In situations when cancer is not curable, palliative chemotherapy can often reduce symptoms caused by tumors.

Below are some of the most comonly used classes of chemotherapy agents:

Mitotic inhibitors can either disrupt mitosis, a type of cell division, or block enzymes from producing proteins needed for cell growth. Mitotic inhibitors, including taxanes, such as Taxol® (paclitaxel) and Taxotere® (docetaxel), and a class of drugs called vinca alkaloids, treat several solid tumors, lymphoma and leukemia. These drugs include Velban® (vinblastine) and Oncovin® (vincristine) and are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect.

Alkylating agents are active against bloodrelated cancers, such as non-Hodgkin’s lymphoma, Hodgkin’s disease, chronic leukemias and multiple myeloma, but are also effective in breast, ovarian and lung cancer. Cisplatin, Cytoxan® (cyclophosphamide) and Ifex® (ifosfamide) are alkylating agents that work by damaging the DNA of cancer cells to prevent them from dividing and multiplying.

Antimetabolites are in a class of drugs that interfere with DNA and RNA growth in cells. Common examples include Gemzar® (gemcitabine), 5-FU (fluorouracil), Cytosar-U® (cytarabine) and Alimta® (pemetrexed). These agents are only effective in a specific cycle of cell growth and are used to treat leukemia, ovarian cancer, certain breast cancers and cancer of the gastrointestinal tract.

Topoisomerase inhibitors, such as Camptosar® (irinotecan) and Hycamtin® (topotecan), interfere with certain enzymes called topoisomerases, which are important in accurate DNA replication. They are used to treat certain types of leukemia, as well as lung, ovarian, gastrointestinal and other cancers.

Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These agents treat a variety of tumors and work in all phases of the cell cycle. A major consideration when giving these drugs is the toxic effects they can have on the heart muscle. For this reason, lifetime dose limitations are often placed on these drugs. Adriamycin® (doxorubicin), Ellence® (epirubicin) and Daunomycin HCL® (daunorubicin) are the more commonly used anthracyclines.

Radiation

Radiation therapy is occasionally used alone in the treatment of some cancers, such as prostate or cervical cancer, but is most often used in combination with other therapies for many cancer types. High doses of radiation may cause side effects even after treatment as well as second cancers, so newer techniques target radiation more accurately to tumor sites in order to minimize these effects.

Various types of targeted radiation include:

Brachytherapy involves radiating the tumor directly from implanted radioactive seeds implanted near the tumor site. Brachytherapy is used in prostate cancer, cervical cancer and rarely in breast cancer. Partial breast irradiation can be accomplished by brachytherapy within the lumpectomy cavity.

Conformal radiotherapy employs several weak beams of radiation originating from different angles that intersect to produce a concentrated high dose of radiation at the tumor site.

Intensity-modulated radiation therapy is an advanced type of conformal radiotherapy that uses multiple beams with varying intensity.

Stem Cell Transplant

Referred to as bone marrow transplant for many years, the term used today is hematopoietic stem cell transplant. Bone marrow, the spongy material inside the bone, is the natural home for hematopoietic stem cells, which are the parental cells that develop into red blood cells that carry oxygen, white blood cells that fight infection and platelets that help the blood to clot. Patients with leukemia, myeloma, lowgrade lymphoma, myelodysplastic syndromes and, less often, various other cancers, may be treated with a stem cell transplant.

High doses of chemotherapy and/or radiation have the unwanted side effect of damaging a patient’s bone marrow stem cells. Thus, stem cell transplants “rescue” patients from this high-dose treatment. Transplantation of stem cells from a related or unrelated donor whose tissue type matches that of the patient is known as an allogeneic transplant. Returning stem cells from the patient’s own body after high-dose treatment is known as an autologous transplant.

If the cells are taken from the patient, they are frozen and stored for later use. If the stem cells are obtained from a donor, they are usually infused in the patient soon after collection and may not need to be frozen. The cells find their way to the bone marrow, where they divide and mature into cells normally produced by healthy bone marrow in a process known as engraftment.

Graft-versus-host disease, or GVHD, may occur in allogeneic transplants when the donor immune cells view the recipient’s body as foreign. The recipient’s immune system has largely been destroyed by conditioning treatment and cannot fight back. The donor immune cells may attack certain organs, most often the skin and liver, which impairs the organs’ ability to function and increases the chance of infection. Acute GVHD occurs 10 to 70 days after a transplant, though the average time is around 25 days. About one-third to half of allogeneic transplant recipients develop acute GVHD.

Hormone Therapy

Hormone therapy is used in cancer to reduce the level of sex hormones in the body and can be used by itself or as adjuvant therapy.

Women with hormone-dependent breast cancer—cancer fueled by estrogen—are commonly treated with tamoxifen followed by chemotherapy if the disease progresses. Taking tamoxifen after surgery, usually for five years, reduces the chance of the cancer coming back by about 50 percent for women with early breast cancer, if the cancer contained estrogen or progesterone receptors.

Aromatase inhibitors are often used in the treatment of early or advanced breast cancer and include Femara® (letrozole), Arimidex® (anastrozole) and Aromasin® (exemestane). They work by blocking an enzyme responsible for producing small amounts of estrogen in postmenopausal women. Since they cannot stop the ovaries of premenopausal women from producing estrogen, aromatase inhibitors are only effective in postmenopausal women.

Prostate cancer patients may receive androgen deprivation therapy, such as luteinizing hormonereleasing hormone (LHRH) analogs and LHRH antagonists, to lower testosterone levels. Surgery can also quickly reduce the levels of sex hormones by removing the ovaries or testicles.

Targeted Therapy

As researchers have learned more about the specific molecular changes responsible for the abnormal growth and spread of cancer cells, they have been able to develop new drugs that target cancer cells more specifically than traditional chemotherapy. Unfortunately, many of these newer agents must be combined with traditional chemotherapy and carry their own side effects, such as rash, heart damage or high blood pressure.

Scientists are now using targeted agents not based on the type of cancer, but based on proteins overexpressed by the tumor.

Various types of targeted therapy include:

Monoclonal antibodies were among the first targeted agents. In 1975, British researchers figured out how to mass produce antibodies of a single (mono) type in the laboratory. At first, these “monoclonal” antibodies, sometimes abbreviated as MoAbs or MAbs, were made entirely by mouse cells, so the human immune system recognized them as foreign and mounted a response against them, possibly causing allergic-type reactions. In the long term, this means the body’s immune system is primed to destroy them before they can be helpful.

Over time, researchers learned how to replace some parts of these mouse antibody proteins with human parts. Some MAbs are now fully human and are likely to be safer and more effective than older MAbs. An even newer approach uses fragments of antibodies instead of whole ones to better reach a tumor. In the past 10 years or so, the Food and Drug Administration approved several MAbs for the treatment of cancer, including Rituxan® (rituximab) for non-Hodgkin’s lymphoma, Herceptin® (trastuzumab) for HER2-positive breast cancer, Erbitux® (cetuximab) for advanced colorectal and head and neck cancer and Vectibix® (panitumumab) for colorectal cancer. Zevalin® (ibritumomab tiuxetan) and Bexxar® (tositumomab), both for non-Hodgkin’s lymphoma, are currently the only radioactive antibody-based drugs approved by the FDA. These drugs use MAbs that target a radioactive atom to the cancer cells.

Angiogenesis inhibitors work by preventing angiogenesis, or the formation of new blood vessels in the tumor. This strategy shuts down a tumor’s blood supply to eliminate the tumor, because tumors, like normal tissue, need nutrients and oxygen from blood to survive. Researchers have been working on drugs to attack cancer in this way, but Avastin® (bevacizumab) was the first successful one. Avastin is approved for colorectal cancer and non-small cell lung cancer, and has shown benefit with chemotherapy in clinical studies for a variety of other cancers, including breast.

Most antiangiogenic drugs target either the vascular endothelial cell growth factor, or VEGF— a protein secreted by certain tumors to promote the growth of new blood vessels—or the VEGF receptor, the protein on blood vessel cells that responds to VEGF. For example, Avastin is a MAb that attaches to VEGF and prevents it from activating the VEGF receptor. Other antiangiogenic drugs that are not monoclonal antibodies include Revlimid® (lenalidomide) and Thalomid® (thalidomide), both approved for multiple myeloma, and Sutent® (sunitinib) and Nexavar® (sorafenib) for kidney cancer.

Tyrosine kinase inhibitors are a significant advancement in targeted therapy. A drug called Gleevec® (imatinib) has changed the way doctors treat people with chronic myeloid leukemia. The Philadelphia chromosome is created when the long arms for chromosomes 9 and 22 break off and switch places. The Philadelphia chromosome produces an abnormal molecule that seems to initiate the leukemia called bcr-abl, which is in a class of enzymes called tyrosine kinases. Gleevec works by inhibiting bcr-abl, and almost all patients respond to the oral drug. Side effects are fewer than with traditional chemotherapy or interferon. Tarceva® (erlotinib) is another kinase inhibitor approved for non-small cell lung cancer and pancreatic cancer. It blocks the overexpression of the epidermal growth factor receptor, or EGFR. A new breast cancer drug called Tykerb® (lapatinib) inhibits both EGFR and HER2.

Proteasome inhibitors, such as Velcade® (bortezomib), treat multiple myeloma by blocking multi-enzyme complexes called proteasomes that break down proteins involved in regulating cell processes relevant to cancer. Inhibiting proteasome function increases levels of these regulatory proteins and helps restore some control over abnormal growth, survival and spread of cancer cells.

Immunotherapy uses the body’s immune system to stimulate the production of T cells‚ specialized immune cells that recognize and kill cancer cells. Naturally occurring substances in the body called cytokines have been found to increase T-cell activity and signal the body to produce more T cells. Some cytokines, such as interleukins and interferons, can be produced in the laboratory for treating kidney cancer, melanoma and bladder cancer.