Making Sense of Cancer Therapies

Scientists continue to learn more about cancer’s biology and how it affects each patient. As they make new discoveries, they are able to refine existing treatments and develop new ones. In addition, research continues to lead to new combinations of different types of drugs that fight cancer more effectively together, such as pairings of chemotherapy with radiation or groupings of chemotherapy with immunotherapy and a targeted drug.

Surgery

In many cases, surgery can be used to remove a tumor and, depending on the pathology of the cancer, the surrounding tissue. In some circumstances, patients might be eligible for less invasive surgical options.

Laparoscopic surgery requires one or more small incisions that allow a thin fiber-optic scope, called a laparoscope, and specially designed surgical instruments to be inserted into the body to remove the tumor. Disease-free survival and recurrence rates for specific tumor types and stages seem to be about the same with laparoscopic surgery compared with traditional open surgery. The main benefits are faster recovery times, shorter hospital stays and fewer complications. A similar technique, used for lung and other thoracic cancers, is thoracoscopic surgery, during which a tiny camera and surgical instruments are inserted through a thin incision in the chest wall.

Robot-assisted surgery could have even more benefits for some patients. As with laparoscopic surgery, robot-assisted procedures require a few small incisions. But instead of directly manipulating the surgical instruments, the surgeon sits at a console to perform the procedure by directing robotic arms. The process enables finer movements yet prevents the surgeon from feeling the tissue in the same way as in open surgery. In addition to prostatectomy (surgery to remove the prostate gland), robot-assisted surgery can be used for hysterectomy to treat cervical and endometrial cancers, and to treat some bladder, throat, thyroid and kidney cancers. When performed correctly by well-trained surgeons in appropriate patients, robot-assisted procedures have the potential to prevent some short-term complications, such as blood loss, and to reduce the length of hospital stays compared with open surgery.

Radiofrequency ablation, or RFA, is an outpatient procedure that uses heat delivered through a thin, needle-like probe inserted into the tumor to kill tumor cells. Cryoablation is a similar procedure that uses rapid freezing and thawing to kill the cancer cells.

Radiation Therapy

Radiation therapy is used alone to treat some cancers, but most often in combination with other therapies to improve the cure rate after surgery. Radiation could also be used to allow less extensive surgery or to relieve side effects of advanced cancer. High doses of radiation can cause side effects after treatment, as well as late effects, such as secondary cancers. Newer specialized techniques more accurately target radiation to tumors and minimize these effects.

Targeted Radiation Therapy Types

Brachytherapy radiates the cancer cells directly by implanting radioactive seeds or wires into the body in or near the tumor. Brachytherapy is used in prostate, cervical and other cancers. Brachytherapy can also be used in breast cancer. This is a type of partial breast irradiation and is sometimes used for smaller, lymph node-negative, lower-risk breast cancers.

Radiopharmaceuticals contain radioactive elements that deliver radiation directly to tumors. These injections are approved to treat bone metastases in prostate and thyroid cancers, as well as some types of lymphoma, and to alleviate cancer-related bone pain; these drugs can also be delivered to tumors in the liver.

Conformal radiation uses several weak radiation beams originating from different angles that intersect to produce a concentrated high dose of radiation at the tumor site. Advanced conformal therapy, such as intensity-modulated radiation therapy, uses multiple beams with varying intensity.

Stereotactic radiosurgery, such as Gamma Knife, uses a computer to simultaneously focus about 200 small beams onto a tumor in the brain while the patient’s head is immobilized in a special helmet. A similar technique, known as CyberKnife, bypasses the need for the helmet by using imaging to make adjustments for movements. Gamma Knife is used for small- to medium-sized tumors in the brain, and CyberKnife is employed for larger tumors and tumors in other areas of the body.

Proton beam therapy uses positively charged particles, called protons, that only travel a certain distance. The method allows doctors to control the depth of radiation more precisely and deliver more of it to tumors while sparing nearby healthy tissue. Proton beam therapy is used for some childhood cancers and certain cancers of the brain, central nervous system, eye, head and neck, liver and lung, and some sarcomas. It’s also being investigated in breast, esophageal, prostate and other cancers. More research is needed to determine if side effects are less intense than with older types of radiation.

Chemotherapy

While surgery and radiation target the tumor, chemotherapy targets the whole body systemically through a number of mechanisms of action. New chemotherapy drugs are more effective and less toxic than agents developed 50 years ago, due to greater knowledge about how to deliver them, including optimal dose and frequency of dose, alone and in combination.

Chemotherapy can be given as the primary — or main — treatment for some cancers, such as lymphoma and leukemia. It can also be given after the cancer has been removed as adjuvant therapy, which might improve survival and delay or prevent disease progression. Neoadjuvant chemotherapy is given before surgery to shrink tumors enough to permit less extensive surgery. When cancer is not curable, palliative chemotherapy can often reduce symptoms caused by tumors and help people live longer.

CLASSES OF CHEMOTHERAPY AGENTS

Antimicrotubule agents disrupt mitosis, a phase of cell division in which a cell duplicates and separates the chromosomes in its cell nucleus. Mitotic inhibitors include taxanes and vinca alkaloids (which are approved to treat some solid tumors, as well as lymphomas and leukemias) and epothilones (which are used to treat advanced breast cancer when taxanes no longer work). Mitotic inhibitors are known for their potential to cause peripheral nerve injury (neuropathy), a potential dose-limiting side effect.

Alkylating agents are used to treat blood-related cancers, such as non-Hodgkin lymphoma, Hodgkin lymphoma, chronic leukemias and multiple myeloma, and are also effective in breast, lung, ovarian and some gastrointestinal cancers. Alkylating agents work by damaging the DNA of cancer cells to prevent them from dividing and multiplying. This group includes platinum-based chemotherapies.

Antimetabolites interfere with DNA and RNA production. They are effective in a specific cycle of cell growth and are used against leukemias, lymphomas and cancers of the ovary, breast, gastrointestinal tract and lung.

Topoisomerase inhibitors interfere with enzymes that are important for accurate DNA replication. They are used to treat certain types of leukemia, as well as colorectal, gastrointestinal, lung, ovarian and other cancers.

Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. Anthracyclines treat a variety of tumors and work in all phases of the cell cycle. Because they can damage the heart muscle, anthracyclines have a lifetime dose limitation.

STEM CELL TRANSPLANTATION

Bone marrow, the spongy material inside the bone, is the natural home for hematopoietic stem cells (HSCs), the “parent cells” that develop into different types of blood cells. These stem cells can be retrieved from either the patient (called an autologous transplantation) or a donor (an allogeneic transplantation). Patients who provide their own HSCs have them removed from the bone marrow or the bloodstream prior to chemotherapy and/or radiation, and the cells are frozen for later use. In other cases, the HSCs come from a donor, who might be an identical twin, another close relative (often a sibling), an unrelated person or even an unrelated newborn. Patients with leukemia, myeloma, low-grade lymphoma, myelodysplastic syndromes and, less often, various other cancers, might be treated with stem cell transplantation.

High doses of radiation and/or chemotherapy have the unwanted side effect of damaging a patient’s bone marrow stem cells. Transplantation restores the patient’s bone marrow. Over time, the infused cells divide and mature into cells normally produced by healthy bone marrow, a process known as engraftment. When donor cells mount an immune attack on residual cancer cells, the effect is called graft-versus-tumor.

Graft-versus-host disease, or GVHD, can occur after allogeneic transplantation if 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 can attack certain organs (most often the skin, liver and gastrointestinal tract), which impairs the organs’ ability to function, while the required suppression of the immune system increases the chance of infection.

About one-third to one-half of patients who receive an allogeneic transplantation develop acute GVHD within 25 days (on average). Serious cases of uncontrolled GVHD, though uncommon, can be fatal.

HORMONE THERAPY

Hormone therapies interfere with the interaction of sex hormones (androgens and estrogens) and some types of cancer, particularly breast and prostate. Hormone therapy can be used alone or with other treatments.

Following surgery, women with breast cancer that is shown to be fueled by estrogen are treated with an estrogen blocker and/or drugs called aromatase inhibitors. These drugs are taken for at least five years. Aromatase inhibitors block an enzyme that converts androgens to estrogens in postmenopausal women.

Patients with prostate cancer could receive androgen-deprivation therapy to lower testosterone levels. Another group of drugs, known as anti-androgens, are sometimes helpful if other hormone therapies stop working. Removing the ovaries or testicles can also reduce the level of sex hormones.

TARGETED THERAPY

Researchers have learned more about specific molecular changes responsible for cancer growth, resulting in new drugs called targeted therapies. These drugs target genes or proteins in the cell. However, many of these newer agents must be combined with traditional chemotherapy, and some carry their own side effects, such as rash, diarrhea, heart malfunction or high blood pressure.

Angiogenesis inhibitors prevent the formation of new blood vessels to the tumor (angiogenesis). Shutting down its blood supply shrinks the tumor, which needs nutrients and oxygen from blood to survive and grow. Most anti-angiogenic drugs target either a protein secreted by certain tumors to promote the growth of new blood vessels (called vascular endothelial growth factor, or VEGF) or the VEGF receptors on blood vessel cells.

Kinase inhibitors block enzymes with a variety of functions, including angiogenesis, growth factor receptors and other aspects of cell signaling, and are used in treating many types of cancer.

Proteasome inhibitors treat multiple myeloma and mantle cell lymphoma by blocking multi-enzyme complexes called proteasomes. These molecules break down proteins involved in regulating cell processes relevant to cancer.

mTOR inhibitors block a key protein in cells that regulates cell growth and survival. These inhibitors block the translation of genes that regulate the cell cycle and reduce levels of certain growth factors involved in the development of new blood vessels, such as VEGF. mTOR inhibitors are currently used for breast, kidney, neuroendocrine and other cancers.

PARP inhibitors block the activity of an enzyme that helps cancer cells repair their DNA when it’s damaged. This can cause the cells to die. Often, these drugs work well in cancers with inherited or acquired mutations to the BRCA genes, because these cancers already have DNA repair problems and the medications further interfere with that process. PARP inhibitors are used to treat breast, ovarian, pancreatic and prostate cancers.

Histone deacetylase inhibitors interfere with the activity of specific proteins to stop cancer cells from repairing their DNA when it’s damaged and change the way certain genes express themselves. This harms the ability of cancer cells to function, preventing them from growing and multiplying. These drugs are approved to treat multiple myeloma and T-cell lymphoma.

Monoclonal antibodies are laboratory-manufactured versions of natural human antibodies, proteins made by the immune system to fight invaders such as cancer. Monoclonal antibodies are designed to seek out and bind to antigens, or markers, on the surfaces of cancer cells, thus stimulating the immune system to attack those cells. These drugs are approved to treat many cancer types, including breast, blood and colorectal.

Antibody-drug conjugates combine two kinds of drugs. One type are monoclonal antibodies, targeted immunotherapies that use natural substances or engineered alternatives to boost the immune system and fight cancer. They have been approved
by the Food and Drug Administration (FDA) for many types of cancer. Antibody-drug conjugates use a linker to attach one of these drugs to a potent chemotherapy agent. The antibody delivers the chemotherapy to cancer cells, and, once the drug is absorbed by the cells, the linker releases the chemotherapy. The FDA has approved this type of treatment for HER2-positive breast cancer and certain types of lymphoma.

IMMUNOTHERAPY

Drugs that stimulate the body’s immune system to attack cancer are known as immunotherapies. In the pages immediately ahead, we explore immunotherapy types including checkpoint inhibitors and chimeric antigen receptor (CAR)-T cell therapy.

WEARABLE DEVICES

Wearable therapeutic devices are newer techniques. One of them, Optune, is approved to treat the brain cancer glioblastoma. Designed to be worn 18 hours a day, the device uses tumor-treating electromagnetic fields to prevent cancer DNA from dividing and multiplying.

A product called Quell is for cancer pain. It wraps around the calf and sends low-frequency electricity to sensory nerves, causing the brain to block pain signals.

Other wearable devices include scalp cooling caps, worn for a period of time before, during and after chemotherapy infusions to help prevent hair loss. Additionally, devices that may detect certain types of cancer are being studied.

NEOADJUVANT AND ADJUVANT TREATMENTS ENHANCE PRIMARY THERAPY

It is becoming more common for patients with cancer to get neoadjuvant and adjuvant treatments, which are given before and/or after the main therapy. These therapies are used in cancers including breast, lung, bladder, colon and ovarian.

Neoadjuvant treatments are often given before surgery to shrink a tumor so it is easier to fully remove. In some cases, the amount of shrinkage affects subsequent treatment decisions. The goal of adjuvant treatment is to prevent recurrence or spread by killing any cancer cells that linger after the primary treatment, which in many cases is surgery.

A number of treatments can be used as neoadjuvant or adjuvant therapies, including chemotherapy, targeted drugs, radiation and hormone-blocking medications. Immunotherapy is available as an adjuvant therapy and is being studied as a potential neoadjuvant treatment.

These before-and-after treatments are given when scientific evidence shows that they are likely to improve health outcomes based on the cancer’s type and stage. They are typically given to patients whose cancer has grown past the very earliest stage, so there is a risk it could leave cells behind after primary treatment, but not to the metastatic stage, meaning it has reached distant parts of the body. Patients with cancers driven by mutations associated with a high risk of recurrence might also benefit from neoadjuvant and/or adjuvant treatments.

Like primary treatments, these types of treatments can cause side effects, so patients should talk with a doctor about the types of therapies recommended, how much they are expected to lower risk of recurrence or cancer death, how they will affect daily life and for how long.