Radiation therapy: the story on HearLore

Radiation therapy

In 1896, Emil Grubbe of Chicago became the first American physician to use X-rays to treat cancer, launching a medical revolution that would unfold over the next century without fully understanding the dangers involved. Before the 1920s, the hazards of radiation exposure were largely unknown, and doctors applied radiotherapy to a wide range of diseases, believing radium possessed wide curative powers. The field began to grow largely due to the groundbreaking work of Marie Curie, who discovered the radioactive elements polonium and radium in 1898, initiating a new era in medical treatment. During this early period, radium was so rare and expensive that in 1937, the entire world supply for radiotherapy was only 50 grams, valued at 800,000 pounds or 50 million dollars in 2005 currency. The first practical sources of radiation were radium, its emanation radon gas, and the X-ray tube, with external beam radiotherapy beginning at the turn of the century using relatively low voltage machines under 150 kilovolts. As the need for deeper penetration grew, orthovoltage X-rays using 200 to 500 kilovolts were adopted in the 1920s, but reaching deeply buried tumors required energies of 1 megavolt or above, necessitating huge, expensive installations. One of the first megavolt X-ray units, installed at St. Bartholomew's hospital in London in 1937, utilized a 30-foot long X-ray tube and weighed 10 tons, remaining in use until 1960. The invention of the nuclear reactor during the Manhattan Project in World War 2 made the production of artificial radioisotopes possible, leading to Cobalt therapy which revolutionized the field between the 1950s and the early 1980s. Cobalt-60 machines were relatively cheap and robust, though their 5.27-year half-life required replacement approximately every five years. Medical linear particle accelerators, developed since the 1940s, began replacing X-ray and cobalt units in the 1980s, with the first medical linear accelerator used at the Hammersmith Hospital in London in 1953. These modern machines produce higher energies and more collimated beams without generating radioactive waste, marking a significant shift from the early days of trial and error to precision medicine.

The Science of Destruction

Radiation therapy works by damaging the DNA of cancer cells, causing them to undergo mitotic catastrophe, a process that can be either direct or indirect ionization of the atoms making up the DNA chain. Indirect ionization occurs as a result of the ionization of water, forming free radicals, notably hydroxyl radicals, which then damage the DNA. While cells have mechanisms for repairing single-strand DNA damage, double-stranded DNA breaks are much more difficult to repair and can lead to dramatic chromosomal abnormalities and genetic deletions. Cancer cells are generally less differentiated and more stem cell-like, reproducing more than most healthy differentiated cells, and possessing a diminished ability to repair sub-lethal damage. Single-strand DNA damage is passed on through cell division, causing damage to the cancer cells' DNA to accumulate, leading to cell death or slower reproduction. One of the major limitations of photon radiation therapy is that cells of solid tumors often become deficient in oxygen, a state known as hypoxia. Tumor cells in a hypoxic environment may be as much as 2 to 3 times more resistant to radiation damage than those in a normal oxygen environment. Oxygen is a potent radiosensitizer, increasing the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. Much research has been devoted to overcoming hypoxia, including the use of high pressure oxygen tanks, hyperthermia therapy, blood substitutes that carry increased oxygen, and hypoxic cell radiosensitizer drugs such as misonidazole and metronidazole. Charged particles such as protons and boron, carbon, and neon ions can cause direct damage to cancer cell DNA through high linear energy transfer and have an antitumor effect independent of tumor oxygen supply. Due to their relatively large mass, protons and other charged particles have little lateral side scatter in the tissue, meaning the beam does not broaden much and stays focused on the tumor shape, delivering small dose side-effects to surrounding tissue. They also more precisely target the tumor using the Bragg peak effect, which sets a finite range for tissue damage after the tumor has been reached. In contrast, intensity-modulated radiation therapy's use of uncharged particles causes its energy to damage healthy cells when it exits the body, increasing the probability of secondary cancer induction. This difference is particularly important in cases where the close proximity of other organs makes any stray ionization very damaging, such as in head and neck cancers. Children are around 10 times more sensitive to developing secondary malignancies after radiotherapy as compared to adults, due to their growing bodies.

Who was the first American physician to use X-rays to treat cancer?

Emil Grubbe of Chicago became the first American physician to use X-rays to treat cancer in 1896. This event launched a medical revolution that unfolded over the next century without fully understanding the dangers involved.

When did Marie Curie discover the radioactive elements polonium and radium?

Marie Curie discovered the radioactive elements polonium and radium in 1898. Her groundbreaking work initiated a new era in medical treatment and caused the field of radiation therapy to grow largely.

How does radiation therapy damage cancer cells at the DNA level?

Radiation therapy works by damaging the DNA of cancer cells, causing them to undergo mitotic catastrophe through direct or indirect ionization of the atoms making up the DNA chain. Indirect ionization occurs as a result of the ionization of water, forming free radicals that damage the DNA.

What is the half-life of Cobalt-60 machines used in radiation therapy?

Cobalt-60 machines have a half-life of 5.27 years. This duration required replacement approximately every five years during the period when Cobalt therapy revolutionized the field between the 1950s and the early 1980s.

When was Volumetric modulated arc therapy introduced to the medical field?

Volumetric modulated arc therapy was introduced in 2007. This technique can achieve highly conformal dose distributions on target volume coverage and sparing of normal tissues by rotating the gantry 360 degrees and changing the speed and shape of the beam.

Which cancer types are routinely treated with curative doses of radiation therapy?

Many common, moderately radioresponsive tumors are routinely treated with curative doses of radiation therapy if they are at an early stage, including non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer.

The Precision Revolution

The planning of radiation therapy treatment has been revolutionized by the ability to delineate tumors and adjacent normal structures in three dimensions using specialized CT and MRI scanners and planning software. Virtual simulation, the most basic form of planning, allows more accurate placement of radiation beams than is possible using conventional X-rays, where soft-tissue structures are often difficult to assess. An enhancement of virtual simulation is 3-dimensional conformal radiation therapy, in which the profile of each radiation beam is shaped to fit the profile of the target from a beam's eye view using a multileaf collimator. When the treatment volume conforms to the shape of the tumor, the relative toxicity of radiation to the surrounding normal tissues is reduced, allowing a higher dose of radiation to be delivered to the tumor than conventional techniques would allow. Intensity-modulated radiation therapy is an advanced type of high-precision radiation that is the next generation of 3-dimensional conformal radiation therapy. It improves the ability to conform the treatment volume to concave tumor shapes, for example when the tumor is wrapped around a vulnerable structure such as the spinal cord or a major organ. Computer-controlled X-ray accelerators distribute precise radiation doses to malignant tumors or specific areas within the tumor, with the pattern of radiation delivery determined using highly tailored computing applications. The radiation dose intensity is elevated near the gross tumor volume while radiation among the neighboring normal tissues is decreased or avoided completely. This results in better tumor targeting, lessened side effects, and improved treatment outcomes than even 3-dimensional conformal radiation therapy. Volumetric modulated arc therapy, introduced in 2007, can achieve highly conformal dose distributions on target volume coverage and sparing of normal tissues by rotating the gantry 360 degrees and changing the speed and shape of the beam. Temporally feathered radiation therapy, introduced in 2018, aims to use the inherent non-linearities in normal tissue repair to allow for sparing of these tissues without affecting the dose delivered to the tumor. New techniques are being developed to better control uncertainty, such as real-time imaging combined with real-time adjustment of the therapeutic beams, known as image-guided radiation therapy. Some techniques involve the real-time tracking and localization of one or more small implantable electric devices implanted inside or close to the tumor, such as magnetic transponders or small wireless transmitters. These technologies allow for the correction of positional errors and account for internal movement caused by respiration or bladder filling, ensuring the radiation hits the target with extreme accuracy.

The Hidden Cost of Survival

Despite the risks, radiation therapy has become a cornerstone of cancer treatment, with half of the United States's 1.2 million invasive cancer cases diagnosed in 2022 receiving radiation therapy in their treatment program. The response of a cancer to radiation is described by its radiosensitivity, with highly radiosensitive cancer cells like leukemias and most lymphomas being rapidly killed by modest doses of radiation. The majority of epithelial cancers are only moderately radiosensitive, requiring a significantly higher dose of radiation between 60 and 70 gray to achieve a radical cure. Some types of cancer are notably radioresistant, such as renal cell cancer and melanoma, but radiation therapy is still a palliative option for many patients with metastatic melanoma. Combining radiation therapy with immunotherapy is an active area of investigation and has shown some promise for melanoma and other cancers. It is important to distinguish the radiosensitivity of a particular tumor from the radiation curability of a cancer in actual clinical practice. For example, leukemias are not generally curable with radiation therapy because they are disseminated through the body, whereas lymphoma may be radically curable if it is localized to one area of the body. Many common, moderately radioresponsive tumors are routinely treated with curative doses of radiation therapy if they are at an early stage, including non-melanoma skin cancer, head and neck cancer, breast cancer, non-small cell lung cancer, cervical cancer, anal cancer, and prostate cancer. With the exception of oligometastatic disease, metastatic cancers are incurable with radiation therapy because it is not possible to treat the whole body. The impact of radiotherapy varies between different types of cancer and different groups. For breast cancer after breast-conserving surgery, radiotherapy has been found to halve the rate at which the disease recurs. In pancreatic cancer, radiotherapy has increased survival times for inoperable tumors. The precise treatment intent, whether curative, adjuvant, neoadjuvant therapeutic, or palliative, will depend on the tumor type, location, and stage, as well as the general health of the patient. Total body irradiation is a radiation therapy technique used to prepare the body to receive a bone marrow transplant, while brachytherapy minimizes exposure to healthy tissue during procedures to treat cancers of the breast, prostate, and other organs. Radiation therapy has several applications in non-malignant conditions, such as the treatment of trigeminal neuralgia, acoustic neuromas, severe thyroid eye disease, pterygium, pigmented villonodular synovitis, and prevention of keloid scar growth, vascular restenosis, and heterotopic ossification. New techniques such as proton beam therapy and carbon ion radiotherapy which aim to reduce dose to healthy tissues will lower the risks of secondary malignancies. These charged particles have little lateral side scatter in the tissue, meaning the beam does not broaden much and stays focused on the tumor shape, delivering small dose side-effects to surrounding tissue. They also more precisely target the tumor using the Bragg

The Human Toll and Triumph

peak effect, which sets a finite range for tissue damage after the tumor has been reached. In contrast, intensity-modulated radiation therapy's use of uncharged particles causes its energy to damage healthy cells when it exits the body, increasing the probability of secondary cancer induction. This difference is particularly important in cases where the close proximity of other organs makes any stray ionization very damaging, such as in head and neck cancers. Children are around 10 times more sensitive to developing secondary malignancies after radiotherapy as compared to adults, due to their growing bodies. The use of radiation therapy in non-malignant conditions is limited partly by worries about the risk of radiation-induced cancers, but new techniques are being developed to better control this uncertainty. In 2024, the United States Food and Drug Administration approved Lutathera, invented by Novartis, for pediatric patients aged 12 or older with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Pluvicto, also invented by Novartis, was approved for metastatic castration-resistant prostate cancer in March 2022. The field continues to evolve with automated treatment planning becoming an integrated part of radiotherapy treatment planning, using knowledge-based planning and protocol-based planning to mimic an experienced treatment planner. Real-time tracking and localization of implantable electric devices are being used to account for internal movement caused by respiration or bladder filling, ensuring the radiation hits the target with extreme accuracy. Deep inspiration breath-hold is commonly used for breast treatments where it is important to avoid irradiating the heart, and 4DCT imaging is used to plan treatments with margins that account for motion. The future of radiation therapy lies in the ability to deliver higher doses to the tumor while sparing normal tissues, reducing side effects, and improving survival rates. More than half of patients in low and middle income countries still do not have available access to the therapy as of 2017, highlighting the need for global expansion of these advanced techniques. The field of radiation oncology is distinct from radiology, the use of radiation in medical imaging and diagnosis, and is concerned with prescribing radiation with intent to cure or for adjuvant therapy. A physician who practices in this subspecialty is a radiation oncologist, and practicing radiographers are therapeutic radiographers. The American Society for Radiation Oncology launched a safety initiative called Target Safely in 2010 to record errors nationwide so that doctors can learn from each and every mistake and prevent them from recurring.