ALL the technicals
Diagnosis
Breast cancer is the most common type of cancer diagnoses in women in the United States. Identifying cancer as early as possible to increase the chance for cure, is the goal of self-exams and screening mammograms. Not all cancers can be felt and not all are visible on mammogram. The mammogram will see a tumor about 85% of the time. Deb’s was not felt or seen on mammogram but there was some skin thickening. The next test for finding a breast lesion that is suspected is either ultrasound or MRI. Her ultrasound saw the mass deep in the breast. The tumor size on the ultrasound was 2.6 cm in maximum diameter. The size is most often reported in centimeters (cm) or millimeters (mm) (1 inch = 2.54 centimeters = 25.4 millimeters). Enlarged lymph nodes can also be seen on the ultrasound and can sometimes appear suspicious for having tumor cells in them. She had 3 or 4 that appeared this way. They were small and not able to be felt. In addition to the standard screening digital mammogram and ultrasound, a digital breast tomosynthesis was done. This is similar to a standard mammogram in that it uses X-ray technology and applies the same amount of pressure to the breast, however, it creates a more detailed, wider view of the breast tissue by creating a 3-dimentional computer enhanced picture of the breast. The 3D technique moves the X-ray tube in an arc around the breast obtaining nine cross-sectional images instead of the usual two views from top to bottom and side to side. The technology is approved by the U.S. Food and Drug Administration as a screening tool for breast cancer, but is not yet considered standard of care and is often not covered by insurance.
Biopsy
Once a mass is found, the next step is to get a piece of it by way of a biopsy. This can be done by way of a needle or an excision. The tissue that is obtained is sent to the pathology lab for evaluation and a great deal of information is obtained. The type of tumor can often be determined by the cell structure seen under the microscope. A tumor can be malignant or benign like a cyst, fibrous material or lipoma. Breast cancer is a malignant tumor that is grouped into two categories called either noninvasive or invasive. Noninvasive or ‘in situ breast cancer’ is the more common and can act benign since it tends to stay in the same spot in the breast. These tumors are considered cancerous because of their tendency to spread locally and become more aggressive if not treated. Women with ductal carcinoma in situ or DCIS are at higher risk (30 percent) for having cancer return following treatment. Most recurrences occur within five to 10 years and it may come back as an invasive tumor.
Invasive or infiltrating breast cancer can spread to surrounding tissue, lobules or ducts and ultimately to other parts of the body through the bloodstream and lymph nodes. Breast cancer is classified based on whether the disease started in the milk ducts (ductal carcinoma - the most common), or lobules (lobular carcinoma). Carcinoma of the breast can be further classified as medullary carcinoma, tubular carcinoma, mucinous carcinoma, metaplastic carcinoma, adenocystic carcinoma. Some less common types of breast cancer include Paget's disease, phyllodes tumor, sarcoma and angiosarcoma.
The pathologist will also grade the cancer cells on how aggressive they appear on a scale of 1 to 3. Grade 3 tumor cells look very abnormal and are the most aggressive. They are fast-growing and are also called poorly-differentiated. Deb’s biopsy showed the tumor was invasive, in the ducts, and grade 3. A biopsy of one of the lymph nodes was also done and was positive for the cancer.
Pathology
The pathologist tested the tumor cells for a number of things. Healthy breast cells contain receptors for the hormones estrogen and progesterone. Hormone receptors are proteins also found in some cancer cells. When hormones attach to hormone receptors in cancer cells, they help the cancer grow, and the cancer is referred to as Hormone receptor-positive. They can be positive for estrogen (ER-positive) and/or progesterone (PR-positive). Hormone receptor-negative breast cancers have few or no hormone receptors. About two out of three women with breast cancer have cells that contain receptors for estrogen and progesterone If the tumor is ER-positive and/or PR-positive, treatment usually includes hormone therapy (such as tamoxifen or aromatase inhibitors) that help prevent or slow tumor growth.
Normal breast cells also contain receptors for a protein called HER2 (human epidermal growth factor receptor 2), which stimulates normal cell growth. This protein is an important part of the pathway for cell growth and survival. About 20 percent of newly diagnosed breast cancers are HER2-positive. HER2-positive cancers can benefit from anti-HER2 drugs, such as trastuzumab (Herceptin), which directly target the HER2 receptor. HER2-negative breast cancers, like Debs’, have little or no HER2 protein and don’t benefit from the drug.
Vascular invasion occurs when cancer cells enter blood vessels or lymph channels, and may indicate a more aggressive tumor. The cell proliferation rate (Ki-67) is the percentage of cancer cells actively dividing. The higher the proliferation rate, the more aggressive the tumor tends to be. Deb had a fairly high proliferation rate indicative of a grade 3 tumor.
About 15 % of all breast cancers are triple-negative where the cancer cells do not have receptors for estrogen, progesterone, or HER2. This type of breast cancer is typically invasive and occurs in the breast ducts as opposed to the lobules. Hormone therapies or medications that work by blocking HER2 are not effective in these cases and the treatment usually involves surgery, chemotherapy, radiation and/or targeted therapies.
Staging
The stage of breast cancer is an important tool in communicating the characteristics of a particular tumor. It gives a common way to describe the breast cancer so the clinician can tell whether it is limited to one area in the breast, has spread inside the breast or to other parts of the body. It helps with understanding prognosis and in making decisions about treatment. It allows comparison with other people with the same diagnosis and sharing of relevant information in clinical trials and research literature. The tumor may be described as localized meaning confined to the breast, regional indicating it is in the breast and lymph nodes in the breast or the armpit, or distant meaning found in other parts of the body.
A standard staging system used in breast cancer is the TNM stage. This system is based on whether the tumor is invasive or not and the size of the tumor (T), whether there are lymph nodes involved with tumor (N), and whether the cancer has spread to other parts of the body or metastasized (M). These are grouped into overall stage I through IV. The rules for each stage group is complicated and based on information collected over many years showing what characteristics can be put together and get a similar prognosis. For instance, Deb’s tumor is stage IIIC based on the finding that the cancer had spread to a lymph node below the collarbone on the PET scan. Stage III breast cancer is divided into subcategories IIIA, IIIB, and IIIC with the criteria for all stage III breast cancer shown below.
Stage IIIA is invasive breast cancer in which either:
no tumor is found in the breast or the tumor may be any size; cancer is found in 4 to 9 axillary lymph nodes or in the lymph nodes near the breastbone (found during imaging tests or a physical exam) OR
the tumor is larger than 5 centimeters; small groups of breast cancer cells (larger than 0.2 millimeter but not larger than 2 millimeters) are found in the lymph nodes OR
the tumor is larger than 5 centimeters; cancer has spread to 1 to 3 axillary lymph nodes or to the lymph nodes near the breastbone (found during a sentinel lymph node biopsy)
Stage IIIB is invasive breast cancer in which:
the tumor may be any size and has spread to the chest wall and/or skin of the breast and caused swelling or an ulcer AND
may have spread to up to 9 axillary lymph nodes OR
may have spread to lymph nodes near the breastbone
Inflammatory breast cancer is a clinical diagnosis and is considered at least stage IIIB
It includes the skin of the breast being red, warm or swollen
spread to the lymph channels found in the skin
Stage IIIC is invasive breast cancer in which:
The tumor may be any size or may have spread to the chest wall and/or to the skin of the breast AND
involves 10 or more axillary lymph nodes OR
has spread to lymph nodes above or below the collarbone OR
has spread to lymph nodes near the breastbone
Imaging
In order to determine whether cancer has spread to other parts of the body radiographic imaging is done. If the tumor is non-invasive or low grade and early stage, this may not be necessary. This can include a whole body PET scan, MRI of the brain, bone scan, or CT scans of the chest abdomen and pelvis.
PET/CT scan for breast cancer creates detailed, computerized pictures of the breasts, allowing us to identify abnormal activity and know precisely where this activity is taking place. This technology offers advanced motion management capabilities and can detect lesions as small as 2.8 millimeters. This advanced nuclear imaging technique combines positron emission tomography (PET) and computed tomography (CT) into once machine. A PET/CT scan reveals information about both the structure and function of cells and tissues in the body during a single imaging session. During a PET/CT scan, the patient is first injected with a glucose (sugar) solution that contains a very small amount of radioactive material. The substance is absorbed by the particular organs or tissues being examined. The patient rests on a table and slides into a large tunnel-shaped scanner. The PET/CT scanner is then able to "see" damaged or cancerous cells where the glucose is being taken up (cancer cells often use more glucose than normal cells) and the rate at which the tumor is using the glucose (which can help determine the tumor grade). The procedure is painless and varies in length, depending on the part of the body that is being evaluated. By combining information about the body's anatomy and metabolic function, a PET/CT scan provides a more detailed picture of cancerous tissues than either test does alone. The images are captured in a single scan which provides a high level of accuracy.
A Brain MRI is often obtained to complete imaging of the whole body. The brain is a very metabolically active organ and takes up a lot of the PET contrast and therefore is not well imaged by the PET scan. The PET scan works because areas in the body that are particularly active like tumors, infections, injuries, and the brain will take up more of the radioactive glucose based contrast than normal tissues and show up on the scan as bright or enhanced areas. The kidney and bladder can collect the contrast and may also be hard to image. If for some reason a PET scan is not able to be obtained, then the body can be imaged by CT of the chest, abdomen and pelvis with a bone scan and brain MRI.
A bone scan can reveal if the breast cancer has spread to the bone. By capturing images of bones on a computer screen or on film, bone scans can reveal important information, such as the location of the bone metastasis. A bone scan is an imaging test that can detect cancerous cells, evaluate fractures in the bones, and monitor other bone conditions, such as infections and arthritis. During a bone scan, a small dose of radioactive material is injected into a vein, where it travels through the bloodstream. The material collects in the bones and is detected by a scanner using nuclear imaging to reveal cell activity and function in the bones. A bone scan can detect cancer that has metastasized to the bone from a different primary site, such as the breast. It may also be used to evaluate bone health before treatment.
Treatment
The treatment for breast cancer will depend on multiple factors. There are guidelines available to help physicians decide on the best treatment options for a particular patient. They provide information on the current standard of care and help find the treatment that will offer the best patience tolerance and chance for cure. Guidelines are usually based on research through national, international and institutional clinical trials and/or physician and institutional experience. One source for this information is the national comprehensive cancer network (NCCN). The NCCN is a not-for-profit alliance of 27 of the world's leading cancer centers that is dedicated to improving the quality, effectiveness, and efficiency of care provided to patients with cancer. The NCCN generates clinical practice guidelines in oncology that are used around the world. Their goal as stated on their web site is to define appropriate treatment pathways based on available resources and deliver a tool for health care providers to identify treatment options that will provide the best possible outcomes. The NCCN guidelines are evidence-based, consensus-driven recommendations made by multidisciplinary expert panels of clinician scientists who practice medicine in the leading academic cancer centers in the United States. NCCN includes input from clinicians around the world who review the guidelines and provide input.
The treatment team consists of a number of people that navigate the patient through the experience of cancer therapy. These can include one or more of the following: Medical Oncologist, Surgeon, Radiation Oncologist, Pathologist, Diagnostic Radiologist, Mammographer, Nurse, Nurse Nvigator, Multidiscipline Coordinator, Genetisist, Nutritionist, Social Worker. Some will find help from other sources such as Pain management, Naturopathic medicine, Mind-body medicine, Oncology rehabilitation, Spiritual support, Survivorship support, Image enhancement
Chemotherapy
Faith and knowledge lean heavily
on each other in the practice of medicine.
Peter Mere Latham
As a kid I once tried to make nitroglycerin from various chemicals around the house but luckily, nothing ever exploded. I enjoyed chemistry class in college and watching the reactions to different chemical combinations. I almost figured out organic chemistry but not
quite; enough for a B. A medical school rotation in medical oncology in the eighties was filled with chemical cocktails that made little sense at the time and I memorized protocols as I watched little if anything happen to the
patients in the short time I was able to observe them – usually just a day or two. It takes a long term view over months and years to get a feel for this kind of practice.
Definition
Chemotherapy consists of drugs that are cytotoxic meaning poisonous to cells.
They work by interfering with the growth of cancer cells that are rapidly dividing, causing damage to the cell’s DNA ideally leading to their death. The problem is that these drugs are also toxic to rapidly dividing normal cells.
Since patient tolerance to drugs and tumor types vary, it is difficult to come
up with a drug or combination of drugs that eliminate the cancer and preserve
the patient. The side effects of chemotherapy are largely due to damage tonormal cells and one of the most sensitive tissues is the bone marrow. When the bone marrow can’t make enough white blood cells, the patient is more prone to infection (immune-compromised or immune-suppressed). The digestive tract is
also very sensitive to chemotherapy. Irritation to these cells causes nausea, vomiting, mouth sores and inflammation (mucositis) and decreased appetite. Hair follicles are rapidly growing cells so damage to them causes hair loss (alopecia), usually temporary.
During chemotherapy one or more anti-cancer drugs and may be given with curative or
palliative intent. The term chemotherapy implies the use of chemicals that are
toxic to cells or cytotoxic. Hormone therapy and targeted therapy are sometimes called chemotherapy but there is a fundamental distinction between the way each works. Cell toxins work by inhibiting cell division or mitosis.
Hormone therapy selectively blocks extra cellular growth signals coming from
endocrine hormones such as estrogen for breast cancer and androgen for prostate
cancer. Targeted therapy, discussed separately, implies the blockade of other growth promoting influences specific to certain cell mutations. The use of drugs to treat disease, especially cancer, (chemotherapy, hormonal therapy or targeted therapy) is called "systemic therapy". The drugs are infused into the bloodstream to treat the whole body. Systemic therapy is often used in
conjunction with local therapy to treat a specific anatomic area where a tumor is known to exist. Local therapy includes surgery, most radiation therapy, cryotherapy, laser ablation, radio-frequency ablation and hyperthermia.
Most chemotherapeutic drugs work by impairing cell division or mitosis making fast
growing cell more sensitive. They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division.One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis. Cells such as cancer with
high growth rates are more sensitive to chemotherapy than most normal cells.
The side effects of treatment occur because some normal cells have growth rates
close to the tumors such as hair and stomach lining cells.
History
The compound “sulfur mustard” was probably first synthesized in a chemistry lab in
Europe in 1854. By 1860 labs were reporting it caused irritation to the eye and skin on contact and to the lining of the mouth and lungs when inhaled. Early in World War I, the Germans began to develop chemical weapons and the
properties of several chemicals including this mustard gas were of interest to the German military. By October 1914, they put small tear-gas canisters in shells and fired them at the town of Neuve Chapelle, France. In January 1915, they killed more than 1,000 soldiers using xylyl bromide, a more lethal gas, on
Russian troops at Bolimov on the eastern front. On April 22, 1915, the German forces attacked two French and Algerian divisions at Ypres, Belgium, using more than 150 tons of chlorine gas. The Germans were as shocked as the Allies by the terrible effects of the poison gas. The US, France and Britain then began
developing their own chemical weapons and defensive measures such as gas masks.
The Germans first developed mustard gas as a weapon in 1917. It was quickly developed and manufactured in large quantities from the chemicals readily available in the chemical dye industry. The gas killed thousands of soldiers.
The United States, which entered World War I in 1917, became interested in this mustard gas compound when it was discovered that contact with it in low concentrations could quickly incapacitate a large number of combat troops. It
was used against the German army in 1918. Military personnel rationalized its use saying it saved lives by reducing the enemy’s ability to mount offensive attacks. More than 100,000 tons of chemical weapons agents were used in World War I, and 500,000 troops were injured, and almost 30,000 died, including 2,000
Americans.
In 1925,the Geneva Protocol of 1925 banned the use of chemical weapons in war. In the
1930s, Italy used chemical weapons against Ethiopia, and Japan used them against China. By the time World War II started effective defenses such as gas masks, protective clothing, and detectors made chemical warfare obsolete. There were now more effective ways to kill the enemy. The Nazis used cyanide gas
(Zyklon B) and carbon monoxide in the concentration and extermination camps and
for its euthanasia program to murder millions. In 1993, an international treaty was signed banning the production, stockpiling, and use of chemical weapons. It took effect in 1997 and has been ratified by 128 nations.
After the war, research into how the gas worked on the body showed that it concentrated
sulfuric acid in cells. The systemic effects on the gastrointestinal tract and bone marrow were described in 1918 and 1919, and the effect on white blood cells was published in 1934. [13] In 1935, Berenblum [1] showed that mustard
gas could slow the growth of tumors in animal studies. During a military operation in World War II, several hundred people were accidentally exposed to mustard gas, and it was found that the survivors had very low white blood cell counts. Yale University and the US. Office of Scientific Research and Development (OSRD), were beginning research on chemical warfare of various types and ways to produce an antidote to mustard gas. Researchers there
proposed that a chemical that can damage the rapidly growing white blood cells might also damage the rapidly growing cancer cells. In December 1942, several patients with a relatively fast growing lymphoma were given the first chemotherapy drug to be synthesized from nitrogen mustard called mustine. The
clinical results were described as remarkable.
Chemotherapy usually refers to cancertreatment, but historically it meant any therapy to treat disease that used a chemical - including antibiotics. The term was first used in the early 1900s by the German physician and scientist Paul Ehrlich (3/14/1854 to 8/20/1915)
who also coined the term “magic bullet”. He helped start the Institute of Experimental
Therapy when the wife of the German Emperor Friedrich II, Princess Victoria, was diagnosed with cancer thus stimulating interest in and financial support for cancer research. Dr. Ehrlich told his sponsors that cancer research meant basic research, and that a cure could not be expected soon. In 1908, he received the Nobel Prize in Physiology or Medicine.
Types
of Chemotherapy Treatment
There are a number of terms used to describe chemotherapy treatment depending on the goal of the treatment or how it is coordinated with other therapies.
Chemotherapy Drugs
O true apothecary!
Thy drugs are quick.
Romeo and Juliet V, iii, 119
Alkylating Agents
Alkylating agents are derived from mustard gas described in the history above, and are the oldest group of chemotherapy drugs in use today. They are named after their ability to bind to molecules, Including DNA and proteins. When a strand of DNA tries to replicate with the
alkylating agent attached it can cause a break leading to the cell’s death. The higher the dose of the drug, the higher the fraction of cells that die. The types of alkylating chemotherapy drugs are listed in the Appendix.
Antimetabolites
Anti-metabolites are a group of molecules that interfere with DNA and RNA synthesis. Because they have a similar structure to DNA and RNA they can block the enzymes required for DNA to divide or become part of the DNA or RNA and cause so much damage the cell dies.
Anti-Microtubule Agents
Microtubules are hollow rod shaped structures that are required for cell division. They are
constantly in a state of assembly and disassembly. Vinca alkaloids are a type
of chemotherapy that prevents the assembly of microtubules, while taxanes are a
type that prevent their disassembly. Both mechanisms cause problems with
mitosis which lead to the cell dying. They also work to stop the growth of blood vessels going to the tumor. Vinca alkaloids - vincristine, vinblastine, vinorelbine, vindesine, and vinflunine - were derived from the Madagascar periwinkle,
Catharanthus roseus or Vinca rosea. Taxanes - paclitaxel and docetaxel - were originally extracted from the Pacific Yew Tree, Taxus brevifolia. They are both now made in laboratories. Podophyllotoxins - etoposide and teniposide - are made from the American
Mayapple, Podophyllum peltatum and Himalayan Mayapple Podophyllum
hexandrum or Podophyllum emodi. They are similar to vinca alkaloids In that they inhibit microtubule formation.
Topoisomerase Inhibitors
Topoisomerase inhibitors prevent DNA from reproducing properly or cause single and
double-strand breaks in DNA both leading to cell death. The drugs in this class
include irinotecan and topotecan,
derived from camptothecin, which is obtained from the Chinese ornamental tree Camptotheca acuminata. Others are etoposide, doxorubicin, mitoxantrone and teniposide. novobiocin, merbarone and aclarubicin are similar but work in a slightly different way.
Antibiotics
The antibiotics used in treating cancer - that are cytotoxic-work by preventing the fast growing cancer cells from reproducing or dividing. The Subgroup called anthracyclines
were obtained from the bacterium
Streptomyces peucetius, and include doxorubicin,
daunorubicin, epirubicin,
idarubicin and
less commonly pirarubicin
and aclarubicin.
Bleomycin, comes from from Streptomyces verticillus. Other
antibiotics used in cancer treatment are mitomycin C, mitoxantrone, and actinomycin.
Drug Resistance
Cancer
Cancer cells are fast growing mutated cells that can potentially change during the
course of treatment. The changed cell population may not respond the same to
the chemotherapy as the original and cause the tumor to be resistant to the
drug. Occasionally a tumor is made up of more than one kind of cell mutation
(multiclonal). One cell type may react differently to a particular drug and
survive the treatment growing a new tumor that is resistant to the
chemotherapy. The exact way these cells survive the drugs is being studied and
may have to do with the presence of small pumps on the surface of the cancer
cells that move the chemotherapy out of the cell, or by gene amplification,
in which so many copies of a gene are produced by the cell that enough survive
and reproduce to grow a new tumor in spite of the chemotherapy. A cell may also
be able to change in such a way that it repairs damage to its DNA or other structures faster than the chemotherapy can cause it. The cancer cells continue to grow in the presence of the chemotherapy. Using multiple drugs that work differently and combining chemotherapy with radiation can make it harder for the cancer cells to become resistant
Radiation therapy
History
Wilhelm Rontgen who was a German mechanical engineer and physicist discovered X-rays in 1895. On 8 November 1895, he was the first to produce and detect or identify a
“new type of rays” as it was called. Röntgen was working with vacuum tubes, and in one experiment, had shielded the tube with a piece of black cardboard. He noticed later that a
bright spot had been produced on a photographic screen (barium platinocyanoide
paper) in the room and concluded correctly that it must have been produced by a new kind of ray when he was working with the vacuum tube. Röntgen was seeing the first radiographic image on the screen. He continued his experiments in secret fearing his professional reputation would be ruined if his observations were wrong. He called the new rays "X-rays", with the mathematical symbol “X” standing for unknown. They were later called
Röntgen rays, but the term X-rays stuck and is still used today. He discovered the rays could pass through various materials and concluded they could also penetrate flesh. A few weeks after his discovery, he placed his wife Anna Bertha's hand in front of the tube and made the first x-ray picture. When she saw the bones in her hand she said "I have seen my
death!” Röntgen's paper, "On a New Kind Of Rays", was published on December 28, 1895. In January 1896, an Austrian newspaper published an article on Röntgen's discovery.
He received the first Nobel Prize in Physics in 1901. A radioactive element roentgenium 111 was later named after him. The roentgen or röntgen (R) is the unit of measurement used today for x-ray exposure.
Antoine Henri Becquerel was a French physicist who started doing experiments
with X-rays. In 1896, he was trying to prove that uranium absorbed the sun’s energy and then emitted it as X-Ray. He ran his experiment one day when it was overcast and noted, to his surprise, that when he developed his photographic plates with no sunlight, the images were still there. This showed
that the radiation came from the uranium and not the sun. Becquerel had discovered radioactivity. He also showed that there were several different types of radiation. He, along with Marie Skłodowska-Curie and Pierre Curie, received the 1903 Nobel Prize in Physics. The unit of measurement for radioactivity, the Becquerel (Bq), is named afterhim. Paul Villard was a French chemist and physicist who discovered gamma radiation in 1900 while studying the radiation emitted by the newly discovered element radium. This was more penetrating than the previous types later called alpha and beta radiation. Most medical use of radiation is gamma.
The term radioactivity was first used by Marie Curie, who together with her husband
Pierre, began investigating the properties of radioactivity. They discovered the elements polonium and radium while working with uranium ore. It took four years of processing tons of ore to isolate enough of each element to determine their chemical properties. Marie Curie won a second Nobel prize for Chemistry in 1911, and in 1912, she published the "Theory of Radioactivity."
The medical use of radiation as cancer therapy began shortly after its discovery, and has been in use for the treatment of cancer and other diseases for approximately 100 years. In 1903, Dr. Charles Leonard noted that X-rays could, “alter the character of malignant cells to prevent their spread and development, and to produce retrograde changes that result in fatty and cystic degeneration or absorption and often terminate in a restoration of the affected part to a nearly normal state.” In other words, treat and potentially cure cancer. [Leonard Cl. The roentgen rays as a palliative in the treatment of cancer. American med 1903; 6:854-855] Marie Curie and Claudius Regaud established the Foundation Curie in 1920 to fund the Institut du Radium. The first hospital, a model for cancer centers around the world, opened in 1922, where Dr. Regaud and his team developed cancer treatments that combine surgery with radiation therapy, focusing on research, teaching and treating cancer.
In 1922, Dr. Coutard successfully treated a patient with laryngeal cancer using radiation showing “acceptable response and side effects”. He developed the technique of giving many daily radiation treatments or “fractions” to give relatively large doses with less side effects. This remains the standard today.
Since the first uses of radiation to treat cancer, there have been many developments made to improve the treatment of cancer patients including the following. Higher energy radiation beams for more effective cancer treatment. The high energy penetrates further and can have less scatter in the body. The
development of the linear accelerator replacing radioactive elements as the source of radiation. The accelerator is turned off when not in use minimizing exposure to physicians and staff and is more versatile. The patient table and machine have been designed to enable
radiation to be delivered to the cancer from a variety of angles and directions to avoid some areas and concentrate dose in others. This includes the use of “beam shaping
devices” that allow the physician to distribute doses of radiation in almost any pattern. The use of medical imaging (CT, PET, MRI, Fluoroscopy, and Ultrasound) creates three-dimensional models to accurately plan and guide treatment. High speed networked computers monitoring and recording the radiation treatments checking for errors and inconsistences and sometimes making modifications in the treatment based on findings. Ultimately the goal is to better target the cancer with lethal doses of radiation while avoiding dose to normal tissues as much as possible. The secondary goal is make treatment fast and efficient and avoid dose to staff.
Characteristics
of Radiation
Radiation
used in the medical field is made up of electromagnetic waves that have enough energy to change the structure of molecules as they pass through them. Electrons become detached from atoms and chemical bonds are broken. The DNA in living cells can be damaged by this ionization process and this can produce temporary or permanent cell damage. Exposure to high doses of radiation can cause damage to living tissue and result in skin burns, hair loss, internal organ failure, genetic damage, cancer and even death. Radiation is not detectable by the human senses.
Radiation Therapy
Radiation Oncology is, according to Halpern and Perez, the discipline of human medicine concerned with the generation, conservation and dissemination of knowledge concerning the causes, prevention and treatment of cancer and other diseases involving special expertise in the therapeutic applications of
ionizing radiation.[]
High-energy ionizing radiation is used to kill the cancer cells by damaging their DNA beyond repair so that the cell stops growing and reproducing and eventually dies. Radiation therapy can damage DNA directly or indirectly by creating free radicles within the cells that then damage the DNA. Through clinical
trials and experience, the radiation oncologist knows what dose will have that
greatest chance of killing the cancer and how much the normal surrounding tissue will tolerate with acceptable side effect. The ultimate goal of radiation therapy is to destroy all the cancer cells without damaging normal
cells. In practice there is always some risk of damage to normal tissue and the dose to the tumor is limited by the dose to the most sensitive surrounding normal tissue.
About fifty percent cancer patients will receive radiation as part of their therapy. Radiation therapy can be given to cure the disease or for palliation. Treatment for cure is designed to destroy all the cancerous cells leaving the patient disease free. With a palliative intent,
the goal is to relieve symptoms caused by the tumor and increase quality of life. Palliative radiation may be used when treating multiple brain tumors causing headached or seizures, to a bone tumor causing pain, a tumor pushing on
the esophagus interfering with eating and/or drinking, or to a tumor in a major
airway making it difficult to breathe. Radiation therapy may be used alone or in combination with surgery, chemotherapy, immunotherapy, targeted therapy and/or complimentary treatments.
Radiation can be delivered to the cancer using several techniques. External-beam radiation therapy (teletherapy), uses a machine outside the body to generate a beamtargeted at the tumor. Internal radiation therapy, or brachytherapy (Greek for short distance), uses a radioactive material placed in the body near
the cancer cells. (or by systemic radiation therapy gives the patient a radioactive substance, such as radioactive iodine or samarium, into a vein that then travels to the cancer cells by way of the blood stream.
External-beam Radiation Therapy
The radiation used for external beam treatment is usually generated by a machine called a linear accelerator or linac.
There are 4 kinds of radiation beams used in the treatment of cancer –
1) Photons or X-rays, 2) Electrons, 3) Protons 4) Neutrons.
Photons
Most External-beam radiation treatment is delivered with photon beams (probably 99%).
A photon can be thought of as a packet of energy. Photons are X-rays
that pass through the breast damaging the tumor cells as they pass through.
Treatment is given with beams that travel across the top of the chest wall to
avoid the heart and lungs. This beam can be generated using a cobalt -60
radiation source but it is less practical to do so because of the potential radiation exposure to staff and the lower energy beam produced.
Electrons
Electrons are radiation beams that treat the skin and do not travel into the body more than a ½ inch or so. They can be used to give radiation to superficial tumors or to the surgical scar if indicated. Electron beams can be generated by the linear accelerator. The electron does not penetrate the body more than a few inches and are therefore used to treat tumors on the skin or close to the surface.
Protons
Protons are heavy charged particles that enter the breast tissue with relative low energy then
deposit all the rest of the energy at a certain depth determined by the treatment plan. In other words, they deposit much of their energy at the end of their path (called the Bragg peak) and deposit less energy along the way. They
clinically act like photons and give the same dose over the same number of treatments. The dose to the tumor is the same as photons and the cure rate is theoretically the same though there is very little data on proton treatment for
breast cancer. The advantage is the there is no radiation given beyond the breast and the dose to the heart and lungs will theoretically be zero. There is however in practice, no evidence that this is actually accomplished with setup variance and breathing. There is also a much greater skin dose given and more side effects seen on the skin. The machine giving the proton treatment cost 120 million dollars compared to 2 million for the photons, so the proton treatment is very expensive (2 to 3 times) and typically not covered by insurance. External-beam radiation therapy can be
delivered by proton beams instead of the photon beams described above. Protons are a heavy charged particle that deposit very little energy in the tissues behind the tumor unlike photons that travel through the patient. There are situations where this is a distinct advantage such as in treatment along the spine and in small children.
Neutrons
Neutron therapy is a highly effective form of radiation therapy. Long-term experience with treating cancer has shown that certain tumors
(pathologies) are very difficult to kill using conventional radiation therapy.
These pathologies are classified as being "radioresistant." Neutron therapy specializes in treating inoperable, radioresistant tumors occurring anywhere in the body.
Hadron therapy ncludes neutrons and protons, which are generated using proton or deuteron
accelerators. Neutrons are high linear-energy-transfer (high LET) radiation and the damage is done primarily by nuclear interactions. If a tumor cell is damaged by low LET radiation it has a good chance to repair itself and continue
to grow. With high LET radiation the chance for a damaged tumor cell to repair itself is very small.
In general, fast neutrons can control very large tumors, because unlike low LET radiation,
neutrons do not depend on the presence of oxygen to kill the cancer cells. In
addition, the biological effectiveness of neutrons is not affected by the time
or stage in the life cycle of cancer cells, as it is with low LET radiation. It often happens that large tumors have metastasized (spread) to other parts of the body before the patient seeks treatment. In these cases neutrons can be
used to control the primary tumor, but chemotherapy must be used to limit the
spread of cancer through the rest of the body.
Because the biological effectiveness of neutrons is so high, the required tumor dose to kill cancer cells is about one-third the dose required with photons, electrons or protons.
A full course of neutron therapy is delivered in only 10 to 12 treatments, compared to 30 - 40 treatments needed for low LET radiation.
The clinical effectiveness of neutrons is limited to slow growing superficial tumors due to toxicity in normal tissue. There few machines in existence and clinical data is minimal.
Consultation
Bring questions. Common questions are: how many treatments, side effects, what do I wear, diet recommendations, medication changes, exercise recommendations, activity level skin creams or lotions, soaps, deodorant, make up, hair coloring, travel, breaks in treatment, exposure to others, sick kids/grand kids, radioactivity, radiation causing cancer.
Simulation
The next step is Simulation. This is needed to design a specific set of radiation beams that target only the area of the body (the one breast) that is to receive the radiation. After removing clothing above the waste and putting on a hospital gown, the patient is placed in a specific position flat on the back with arms over the head. The table is cold hard carbon fiber. To make sure the position is reproducible, a “mold”, like a large bean bag, is made and fitted under the patient and saved for treatment each day. Several “marks” are made on the skin with a marker and covered with tape so they won’t rub off. Then the patient is “scanned” by a CT scanner to put images of the breast and surrounding tissues in the computer to help with designing the beams. Treatment planning takes about 30 minutes. No IV, contrast, or anesthesia is given and the patient does not need to do anything prior to the scan. For tumors in the left breast there is sometimes an advantage to “breath hold techniques” to minimize of eliminate errors in the setup from breathing this can reduce the dose given to the heart and lungs. The goal of the planning is effective destruction of cancer tissue while delivering a minimal dose of radiation to adjacent healthy tissues. Another goal is to make the treatment easier and shorter for the patient to sustain and the physicians and other healthcare professionals to perform.
Treatment Plan
After simulation, the radiation oncologist then determines the exact area that will be treated, the total radiation dose that will be delivered to the tumor, how much dose will be allowed for the normal tissues around the tumor, and the safest angles (paths) for radiation delivery. This is the treatment plan. The radiation oncologist considers a variety of factors when planning the treatment. The patient’s general health and medical history, and the type of cancer may determine the goal of treatment. The size of the cancer, its location in the body, and how close it is to normal tissues are important for the radiation beam design. Care is coordinated with a team of physicians such as surgeons, medical oncologists, pathologists, radiologists, internists, and primary care physicians. Allied health professionals such as nurses, social workers, nutritionists and therapists are included in the team that will
determine whether the patient will have other types of treatment. Patients usually receive external-beam radiation therapy in daily treatment sessions, five per week, over the course of several weeks. The number of treatments depends on the treatment plan generated by the oncologist. It usually takes one or two days for the plan to be completed. The beam can be directed at the tumor when there is no sensitive tissues in the way. Many methods of delivering external-beam radiation therapy are available to the physician to optimize the dose to the tumor while limiting the dose to normal tissues.
Some of the aspects of the plan that may come up in conversation or cause questions or may be overheard are listed here. One of the most common techniques to get around normal tissues that are not to be treated is to use 3- dimensional imaging. Three dimensional conformal radiation therapy or 3D-CRT uses very sophisticated computer software and advanced treatment machines to deliver radiation to very precisely shaped target areas. This is a way to form a very tight margin that conforms closely around the tumor (3 D conformal radiation therapy). A further more sophisticated way of doing this is to use many beams of various intensity from many directions. This is called intensity modulated radiation therapy or IMRT. Intensity modulated radiation therapy or IMRT uses hundreds of tiny radiation beam-shaping devices, called collimators, to deliver a single dose of radiation. This kind of dose modulation uses inverse
treatment planning and allows different areas of a tumor or nearby tissues to receive different doses of radiation giving the doctor the ability to shape the beam around normal tissues. This can reduce the risk of some side effects by reducing the dose to specific tissues outside the tumor. However, it can produce an overall larger volume of normal tissue exposed to low doses of radiation. IMRT is planned in reverse so the radiation oncologist chooses the radiation doses to the tumor and surrounding tissue a head of time, and then the computer calculates the required number of beams and their angles to get the optimal
treatment.
Image guided radiation therapy or IGRT are imaging scans performed daily during the treatment to identify the tumor’s size and location and to allow the position of the patient or the planned radiation dose to be adjusted during treatment as needed. This can increase the accuracy of the treatment and minimize the size of the beam decreasing the total radiation dose to normal tissue. During very conformal treatments it is critical to accurately set up the patient and machine so there is little if any
error in targeting the treatment beams. One way to do this is through image guidance or IGRT (Image Guided Radiation Therapy). IGRT uses images of the patient right before each treatment is given so the physician can confirm that the target is in the correct position. This can also be used to identify changes in a tumor’s size and location due to treatment and to allow changes in the position of the patient or the radiation dose or beam shape as needed. This can increase the accuracy of the beam and allow for more conformal higher dose fields, treating less normal tissue, and thus reducing side effects.
Tomotherapy is a way of combining IGRT and IMRT by allowing the linear accelerator to rotate around the patient like a CT scan. Tomotherapy machines can capture CT images of the patient’s tumor immediately before treatment
sessions, to allow for very precise tumor targeting and sparing of normal tissue.
Stereotactic radiosurgery (SRS) is a method of giving higher doses to a tumor in fewer fractions (usually 1 to 5) using accurate targeting with IGRT, IMRT, very small margins and body immobilization. The resulting higher dose of radiation can be more effective in killing some fast growing tumors without excess damage to normal tissue. SRS is best used to treat small tumors commonly in the brain or
spine. Significant results have been seen in treatment of small lung tumors where studies show 5 year control rates of 85 to 90 %, much higher than radiation given with smaller daily doses over a longer time. Stereotactic body radiation therapy (SBRT) refers to treatment using the same principles but excludes the brain. Treatment can be given using a number of treatment machines including the linear accelerator, Tomotherapy, GammaKnife®, or CyberKnife®. The GammaKnife treats brain tumors with a single dose using many radioactive cobalt sources targeting a point. A headframe is attached to the patient and the treatment table to keep the head from moving. An MRI is used to plan the beams. The
CyberKnife has a small linear accelerator mounted on a robot arm that can move
in virtually any position around the patient.
Patients who receive most types of external-beam radiation therapy usually have to travel to the hospital or an outpatient facility up to 5 days a week for several weeks. One dose (a single fraction) of the total planned dose of radiation is given each day. Occasionally, two treatments a day are given. Most
types of external-beam radiation therapy are given in once-daily fractions. There are two main reasons for once-daily treatment: To minimize the damage to normal tissue. To increase the likelihood that cancer cells are exposed to radiation at the points in the cell cycle when they are most vulnerable to DNA damage.
In recent decades, doctors have tested whether other fractionation schedules are helpful , including: Accelerated fractionation—treatment given in larger daily or weekly doses to reduce the number of weeks of treatment. Hyperfractionation—smaller doses of radiation given more than once a day. Hypofractionation—larger doses given once a day or less often to reduce the number of treatments. Researchers hope that different types of treatment fractionation may either be more
effective than traditional fractionation or be as effective but more convenient.
Verification
Simulation
An appointment to return for a verification simulation is then made. On this day, the patient is placed in a gown and lies on the mold on the treatment table on the accelerator. This same position is used every day during the treatment - flat on the back, on the mold, in a gown, with arms over the head. The verification simulation takes about twenty minutes. New marks and some x-ray films are taken so the doctor can verify that the planned treatment beams are going to go to the right place and are the right shape and size. Usually no actual treatment is given this day, but an appointment date and time is given for the first treatment. A treatment consent is signed if not done during the consultation.
Treatment
Radiation Therapy Treatment is given daily, five days a week, not on weekends or holidays. There may be some variation in the actual number of treatments. It takes about fifteen minutes for the treatment and it is given at the same time each day. There is some tolerance for missed days but an attempt is made to keep this to a minimum. The accelerator has an up time of 98% and is extremely reliable and accurate. It is possible to miss a day or two during the course to treatment because the machine is being calibrated or repaired. It is important to finish the treatment within 60 days according to clinical data, to reduce the chance for recurrence.
The patient sees the radiation oncologist every week during the treatment. He/she will ask about side effects and examine the breast. This is a good time to ask questions. After some treatments, there may be an adjustment to the treatment area planned. This means going back on the simulator like the first day and get new marks over a smaller area around the incision. This is called a boost.
Internal radiation
Internal radiation therapy or brachytherapy, is radiation delivered from
radioactive sources placed inside or on the body. Brachytherapy can deliver
higher doses of radiation to the cancer than external-beam radiation therapy
while causing less damage to normal tissue and may be combined with external
beam treatment. Several techniques are used in brachytherapy. When the
radioactive sources are placed inside a tumor or organ containing the tumor,
the treatment is called interstitial brachytherapy. These are usually permanent seeds and though
the radioactivity goes away over several days or months, the seed holding the
radioactive element is harmless and stays behind. This type of treatment is
used for prostate cancer and some GYN cancers. If the radioactive source is placed in a body cavity like the vagina oruterus it is called intracavitary brachytherapy. These sources are removed after the treatment is over. There may be several treatments and they may last minutes or days depending on the type of source used. Episcleral brachytherapy, which is used to treat cancer in the eye, uses a source that is temporarily attached to the eye. Brachytherapy can be given as a
high-dose-rate treatment where a machine containing a high energy radiation source
attached to delivery tubes placed inside the body guides one or more radioactivesources into or near a tumor, and then removes the sources at the end of each treatment session.
In low-dose-rate treatment, cancer cells receive continuous low-dose radiation from the source over a period of several days.
In high-dose-rate treatment, a robotic. High-dose-rate treatment can be given in one or more treatment sessions. An example of a high-dose-rate treatment is the MammoSite® system, which is being studied to treat patients
with breast cancer who have undergone breast-conserving surgery.
The placement of brachytherapy sources can be temporary or permanent. For permanent brachytherapy, the sources are surgically sealed within the body and left there, even after all of the radiation has been given off. The remaining material (in which the radioactive
isotopes were sealed) does not cause any discomfort or harm to the patient. Permanent brachytherapy is a type of low-dose-rate brachytherapy. An example is the insertion of radioactive seeds in the prostate to treat early prostate cancer.
For temporary brachytherapy, tubes (catheters) or other carriers are used to deliver the radiation sources, and both the carriers and the radiation sources are removed after treatment. Temporary brachytherapy can be either
low-dose-rate or high-dose-rate treatment.
Doctors can use brachytherapy alone or in addition to external-beam radiation therapy to provide a “boost” of radiation to a tumor while sparing surrounding normal tissue.
In systemic radiation therapy, a patient swallows or receives an injection of a radioactive substance, such as radioactive iodine or a radioactive substance bound to a monoclonal antibody. Radioactive iodine is a type of systemic radiation therapy commonly used to help treat some types of thyroid cancer. Thyroid cells naturally take up radioactive iodine. For systemic radiation therapy for some other types of cancer, a monoclonal antibody helps target the radioactive substance to the right place. The antibody joined to the radioactive substance travels through the blood, locating and killing tumor cells. For example: The drug ibritumomab tiuxetan (Zevalin®) has been approved by the Food and Drug Administration (FDA) for the treatment of certain types of B-cell non-Hodgkin lymphoma (NHL). The antibody part of this drug
recognizes and binds to a protein found on the surface of B lymphocytes. The combination drug regimen of tositumomab and iodine I 131 tositumomab (Bexxar®) has been approved for the treatment of certain types of NHL. In this regimen, nonradioactive tositumomab antibodies are given to patients first, followed by treatment with tositumomab antibodies that have 131I attached. Tositumomab recognizes and binds to the same protein on B lymphocytes as ibritumomab. The nonradioactive form of the antibody helps protect normal B lymphocytes from being damaged by radiation from 131I. Many other systemic radiation therapy drugs are in clinical trials for different cancer types.
Some systemic radiation therapy drugs relieve pain from cancer that has spread to the bone (bone metastases). This is a type of palliative radiation therapy. The radioactive drugs samarium-153-lexidronam (Quadramet®) and strontium-89 chloride (Metastron®) are examples of radiopharmaceuticals used to treat pain from bone metastases.
[NCI publications Radiation Therapy and You: Support for
People With Cancer and
the Radiation Therapy Side Effects Series.]
Side effects of Therapy
The side effects experienced during and after radiation therapy are usually caused by damage to the normal tissues surrounding the tumor. Treatment planning by the oncologist is designed to minimize the amount of normal tissue being treated. There are many techniques used to accomplish this as mentioned above. Side effects vary depending on the location of the treatment, the dose given, medications given during treatment, and the individual’s sensitivity to radiation. Things that can increase the side effects of radiation therapy include treatment to areas that are healing or inflamed, previous radiation in the same area, medical conditions such as lupus, diabetes, COPD, and chemotherapy or antibiotics.
Early
side effects
Side effects of the treatment should be explained the first day during the consultation. Radiation therapy can cause both early and late side effects. These are different for everyone and its difficult to predict them. Acute side effects occur during treatment, and chronic side effects occur months or even years after treatment ends. The side effects that develop depend on the area of the body being treated, the dose given per day, the total dose given, the patient’s general medical condition, and other treatments given at the same time. Acute radiation side effects are caused by damage to rapidly dividing normal cells in the area being treated. These effects include skin irritation or damage at regions exposed to the radiation beams. Examples include damage to the salivary glands or hair loss when the head or neck area is treated, or urinary problems when the lower abdomen is treated. Most acute effects disappear after treatment ends, though some (like salivary gland damage) can be permanent. The drug amifostine (Ethyol®) can help protect the salivary glands from radiation damage if it is given during treatment. Amifostine is the only drug approved by the FDA to protect normal tissues from radiation during treatment. This type of drug is called a radioprotector. Other potential radioprotectors are being tested in clinical trials.
Fatigue is a common side effect of radiation therapy regardless of which part of the body is treated. Nausea with or without vomiting is common when the abdomen is treated and occurs sometimes when the brain is treated. Medications are available to help prevent or treat nausea and vomiting during treatment.
Late Side Effects
Late side effects of radiation therapy may or may not occur. Depending on the area
of the body treated, late side effects can include (1):Fibrosis (the replacement of normal tissue with scar tissueleading to restricted movement of the affected area).Damage to the
bowels, causing diarrhea and bleeding.Memory loss.nfertility (inability to have a child). Rarely, a second cancer caused by radiation exposure.
Second cancers that develop after radiation therapy depend on the part of the bodythat was treated. For example, girls treated with radiation to the chest for Hodgkin lymphoma have an increased risk of developing breast
cancer later in life. In general, the lifetime risk of a second cancer is highest in people treated for cancer as children or adolescents.
Whether or not a patient experiences late side effects depends on other aspects of their cancer treatment in addition to radiation therapy, as well as their individual risk factors. Some chemotherapy drugs, genetic risk factors,
and lifestyle factors (such as smoking) can also increase the risk of late side effects.
