Radiation Therapy

Radiation therapy (also known as radiotherapy) is a cancer treatment that uses precisely targeted beams of high-energy radiation to kill cancer cells and shrink tumors [1]. Radiation has been used in medicine since its discovery in the 19th Century both to diagnose (X-rays) and treat cancer (radiation therapy) [2]. Over time, radiation therapy has undergone many technological advances to make delivery more precise, increase safety, and improve treatment outcomes.

Radiation therapy damages the DNA of cancer cells, which blocks their ability to divide and grow [3]. When the genetic material of a cancer cell is damaged beyond repair it will stop dividing and eventually die. Radiation therapy does not kill cancer cells immediately, but rather, it takes weeks or months after treatment for the anticancer effects to be fully realized [1]. Radiation is most commonly applied from a machine outside of the body (called external-beam radiation therapy), normally in the form of X-rays, but sometimes as protons or other energy types [4]. Radiotherapy can also be delivered internally when a sealed radiation source is placed inside the body near tumors (called brachytherapy) [4].

It is estimated that around 50% of all cancer patients can benefit from radiation therapy in the management of their disease [3] [5]. Radiation accounts for about 40% of successful curative cancer treatment 3] [5]. It can be applied with curative intent to eliminate a tumor entirely as or as a palliative therapy to relieve symptoms and improve quality of life [3]. Radiation can destroy tumors and/or help to prevent recurrence [4]. Combination strategies exist where radiation therapy is given in conjunction with surgery, chemotherapy, or immunotherapy [3]. Radiation prior to surgery (neoadjuvant therapy) aims to shrink tumors making them easier to remove, while application after surgery (adjuvant therapy) has the purpose of destroying any remaining microscopic tumor cells [3].

Research shows that radiation therapy is effective for a range of cancer types, especially localized tumors such as breast, lung, prostate, and head and neck cancers. Many clinical trials have demonstrated benefits in terms of survival rates and quality of life. However, radiation therapy can also damage healthy tissues and cause side effects such as fatigue, nausea, difficulty swallowing, hair loss, skin changes, and many others [6]. Adverse effects vary depending on the location and amount of radiation received. In some cases, serious side effects can occur such as infertility, incontinence, sexual dysfunction, organ damage, and secondary cancers [6] [7].

History of Radiation Therapy

The origins of radiation can be traced back to 1895 when Wilhelm Conrad Roentegen discovered a new kind of ray (while working with a cathode-ray tube) that could penetrate through cardboard, but not through lead or platinum [8]. He experimented with these rays and used them to capture a landmark translucent image of his wife’s hand [8]. This famous image marked the discovery of what he termed ‘X-rays’ and gave rise to the fields of radiology and radiation oncology [8]. The first therapeutic uses of X-rays quickly followed Roentgen’s discovery. Just 7 months later in 1896, an issue of Medical Record described a patient with stomach cancer who had benefited from radiotherapy delivered by Victor Despeignes in France [8]. Émil Grubbé, a medical student in Chicago, later claimed to have been the first person to treat cancer patients with X-rays in 1896 [8].

Soon thereafter, Antoine-Henri Becquerel, a professor of physics in Paris, recognized natural radioactivity when working with uranium salts [8]. In 1898, Marie and Pierre Curie discovered radium and polonium, which were even more radioactive than uranium [9].** **For their discoveries, Becquerel shared half of the Nobel Prize for Physics with Marie and Pierre Curie in 1903 [9]. The concept of using radioactive materials to treat cancer was sparked by Becquerel experiencing a severe skin burn in 1901 when he accidentally left a tube of radium in his vest pocket for 14 days [8]. By 1902, radium had been used to successfully treat throat cancer in Vienna and by 1904 radium tubes were being implanted directly into the tumors of patients used in New York, which represent the first brachytherapy (internal radiation) treatments [8]. In 1913, The Standard Chemical Company began marketing radium from Colorado mines as a wonder drug and it found its way into many commercial products [8].

At the time the risks were unknown. No one realized that the rays could be harmful, partly because of the slow onset of symptoms, and also because nobody suspected that an invisible ray similar to light could be harmful [8]. Many actually believed that exposure to radioactivity could be beneficial. However, Pierre Curie noted early complications of radiation exposure in his Nobel Prize lecture where he explained the delayed onset of sores if you put radium salts in your pocket for just a few hours. Longer exposure, he explained, could lead to paralysis and even death [8]. In fact, Curie outlined concerns around radiation falling into criminal hands and being used nefariously in warfare [8]. Both Marie Curie and her daughter Irene later died of radiation related toxicities [8]. Nevertheless, the hazards of radioactivity were slow to gain widespread recognition and acceptance [8].

It has been a long road from the first experiments with X-rays in the late 19th Century to reach the point of the efficacy of modern radiation therapy as a cancer treatment [10]. There have been four major periods of development, which include the German school from 1900 to 1920, the French school from 1920 to 1940, the British school from 1940 to 1960 and the US and European school from 1970 to the present day [10].

During the earliest period, the first treatments were delivered as single large doses using radium and x-ray machines, which was relatively crude compared to modern technology [8]. In the 1920s and 1930s cobalt-60 machines were developed, which enabled more precise and higher-dose radiation therapy [8]. In the 1950s and 1960s linear accelerators were introduced, which could deliver even higher doses with more accuracy [8]. In the 1970s and 1980s, computer-based treatment planning systems were created, which enabled more precise targeting of tumors and reduced collateral damage to healthy tissues [8].

In the 21st Century advances in radiotherapy have continued with the development of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), which have even further increased accuracy and safety. Ongoing research and development will likely continue to improve safety and efficacy of radiotherapy over time.

Research on Radiation Therapy

Radiation therapy forms a central part of standard of care cancer treatment alongside surgery, chemotherapy, immunotherapy, and hormonal therapy [3]. Approximately 50% of all cancer patients can benefit from radiation as part of their treatment programs [3] [5]. It is estimated that radiation contributes towards 40% of curative cancer treatment [3]. Over 14 million new cases of cancer are diagnosed each year around the world, which means radiation has the potential to improve the rate of cure of 3.5 million patients and provide palliative benefits for an additional 3.5 million patients [5].

A 2010 meta-analysis of 6 clinical studies involving 1205 patients found that radiation therapy for non-small cell lung cancer (NSCLC) significantly improved survival rates [11]. The data showed a 16% relative reduction in mortality, corresponding to a 5.7% absolute benefit in overall survival at 3 years and a 4.5% absolute benefit at 5 years (compared to control group), with a survival rate of 18.4% at 3 years and of 15.1% at 5 years. However, acute toxicity was reported in around 4% of patients, which increased to 18% in those receiving chemotherapy at the same time.

A 2016 meta-analysis on radiation for lung cancer (NSCLC) with concurrent chemotherapy analyzed the data of 25 studies involving 3795 patients [12]. It found that in clinical trials where patients received concurrent chemotherapy, progressively higher doses of radiation resulted in poorer survival, which was likely due to high toxicity levels. When radiation therapy was given without chemotherapy, progressively higher doses of radiation resulted in progressively longer survival.

A 2002 study published in the New England Journal of Medicine found that radiation therapy for breast cancer reduced the risk of recurrence in women with early-stage breast cancer [13]. In the trial, a total of 1851 women underwent randomly assigned treatment consisting of total mastectomy (breast removal), lumpectomy (breast-conserving surgery) alone, or lumpectomy and breast irradiation. They were then followed up for 20 years. Incidence of tumor recurrence was 14.3% in the group who underwent lumpectomy combined with radiation compared to 39.2% in the group who underwent lumpectomy without radiation therapy. No significant differences were observed among the three groups of women as regards disease-free survival or overall survival.

While radiation therapy can help patients beat cancer in certain cases, research also shows that it may cause serious side effects. Adverse effects vary depending on the type of cancer and the treatment approach. Radiation for breast cancer can induce fatigue, skin changes, lymphedema, and increase the risk of lung diseases and heart complications [14]. Side effects of radiation for head and neck cancer can include permanent loss of saliva, difficulty swallowing, hypothyroidism, neurological damage, and secondary cancers [15]. Numerous studies have documented that radiation therapy in the pelvic area (for rectal, cervical, ovarian, prostate cancer, etc.) can cause debilitating side effects that can negatively impact quality of life such as incontinence, sexual dysfunction, infertility, hormonal changes, anxiety and depression [15] [16] [17].

Overall, radiation therapy can be an effective and viable treatment option in certain cases, but the risk-benefit profile depends greatly on the type of cancer and location. With advances in technology and the development of more sophisticated treatment approaches side effects are being reduced and outcomes are improving for patients.

Applications of Radiation or Radiotherapy for Cancer

Radiation therapy is considered to be the most effective cytotoxic (kills cancer cells) treatment available for localized solid cancers, which is evidenced by the fact that around 60% of cancer patients in the USA receive radiation therapy with the intention to cure [18]. Radiation can be applied to treat a range of cancer types. It can be used alone (primary treatment) or it can be administered in conjunction with other treatments (adjuvant therapy) such as surgery and chemotherapy. It is most commonly applied with curative intent for cancers that are localized [5]. It can also control cancer growth locally or provide symptom relief (palliative care) in cancers that are locally advanced or widespread [5].

Radiation therapy is an essential part of standard of care curative treatment for cancers of the breast, prostate, cervix, head and neck, lung, and brain, as well as sarcomas [5]. Radiation as a sole therapy is used for localized treatment of early-stage throat cancer, prostate cancer, skin cancer, head and neck cancer, and lymphomas [5]. In more advanced disease stages, radiation therapy is often applied before (neoadjuvant), during (concurrent), or after surgery (adjuvant), and is frequently combined with chemotherapy, either concurrently, or after treatment [5]. Combination therapy has been shown to be beneficial in treating cancers of the lung, cervix, head and neck, vulva, and anal canal [5].

Palliative radiotherapy for the management of symptoms is often applied in multiple myelomas and lymphomas [5]. Radiation can also be applied to control selected metastases (secondary tumors) in cases of advanced metastatic (widespread) cancers [5]. In patients with advanced cancers radiation can alleviate suffering by shrinking tumors that are causing pain or interfering with the ability to eat or drink [4].** **Neoadjuvant therapy aims to shrink tumors to make operations easier, while adjuvant therapy after surgery destroys microscopic tumor cells left behind to reduce risk of recurrence [3].

There are two main ways that radiation therapy can be administered: externally or internally. External beam radiation involves delivering radiation to the tumor site from outside of the body with a machine, while internal radiation therapy (brachytherapy) involves the placement of a radioactive source inside the body near the target tumor [1]. Internal radiation with a liquid source is known as systemic therapy [1]. Systemic means that the radioactive agent travels throughout the body in the bloodstream to tissues and eliminates cancer cells. With systemic radiation the patient’s bodily fluids (sweat, urine, etc.) will continue to give off radiation for a period of time [1].

The type of radiation given to a patient depends on many factors, such as [1]:

• The type of cancer
• Size of the tumor
• Location in the body
• Patient’s general health and medical history
• Other concurrent treatments
• Age and medical conditions

In theory, tumors can be controlled by radiation if sufficiently high doses are given to eradicate the entire cancer stem cell population in a tumor [19]. However, in clinical practice, the collateral damage to surrounding normal tissues and resultant side effects limits the amount of radiation a patient can receive [19]. A major challenge in radiotherapy is to maximize doses to cancer cells while minimizing the damage to nearby healthy tissues [20]. Severe toxicity in a minority of patients limits the potential doses for a large majority of patients. Doses are set to limit toxicity in those that are most sensitive [20]. In general, there is a limit to the amount of radiation your body can safely receive over a lifetime [1]. Depending on how much radiation has been applied to a certain area in the body you may not be able to receive further radiation.

Continued advancements in the computerization of radiotherapy planning and delivery are helping to better target tumors and spare healthy tissues [5]. Newer techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are now allowing for therapeutic doses of radiation to be delivered in only a few high-dose treatments, which results in a higher probability of tumor eradication [5] [18]. Modern higher dose targeted approaches are likely to continue to increase safety and efficacy and improve patient outcomes [18]. Radiation is also being delivered in combination with molecular targeted therapy in an attempt to further improve therapeutic effects [3]. However, radiation still comes with risks and side effects.

Risks and Side Effects of Radiation Therapy

While radiation can kill or slow the growth of cancer cells, it is cytotoxic, which means it can kill or damage all types of cells. Therefore, radiation therapy can also damage nearby healthy cells. This collateral damage can result in side effects, which range from mild to very serious.

Side effects from radiation therapy can happen during or shortly after treatment, which are known as early side effects. Side effects can also take months or years to develop, which are termed late side effects [21].

Patients that undergo radiation therapy commonly experience fatigue, skin problems, hair loss, and low blood counts [21]. These effects can happen immediately or develop progressively over time [6]. Radiation can cause many other side effects, but these vary greatly depending on the part of the body being treated [6].

Radiation therapy for brain cancer can cause [6] [21]:

• Fatigue
• Hair loss
• Concentration issues
• Nausea and vomiting
• Skin changes
• Hearing loss
• Memory loss
• Headache
• Seizures
• Stroke-like symptoms
• Poor brain function

Radiation therapy for breast cancer can cause [6] [14] [21]:

• Skin changes
• Hair loss
• Fatigue
• Swelling (edema)
• Tenderness
• Heart complications
• Lung damage
• Nerve damage
• Increased risk of heart and lung diseases

Radiation to the chest area for lung cancer can cause [6] [21]:

• Skin changes
• Hair loss
• Fatigue
• Difficulty swallowing
• Loss of appetite
• Throat problems
• Cough
• Shortness of breath
• Breathing problems
• Heart damage with increased risk of heart disease
• Heart valve damage
• Lung diseases such as emphysema
• Chest pain

Radiation therapy for head and neck cancer can cause [6] [21]:

• Fatigue
• Sores in mouth or throat
• Hair loss
• Skin changes
• Difficulty swallowing
• Swelling in gums, throat, or neck
• Jaw stiffness
• Taste problems
• Dry mouth
• Hypothyroidism

Radiation to the pelvic area (for cervical cancer, ovarian cancer, prostate cancer, bladder cancer, cervical cancer, vulval cancer, anal cancer, etc.) can cause [6] [17] [21]:

• Diarrhea
• Fatigue
• Hair loss
• Skin problems
• Sexual dysfunction
• Infertility
• Urinary and bladder problems
• Incontinence
• Hormonal issues and mood disorders

Radiation therapy for stomach cancer can cause [6] [21]:

• Diarrhea
• Fatigue
• Hair loss
• Nausea and vomiting
• Cramps
• Constipation
• Skin problems
• Urinary and bladder problems

Radiation therapy can also have serious delayed side effects (late side effects), including vital organ damage, increased morbidity from heart and lung diseases, neurological damage and even increased rates of secondary cancers [14] [15] [22].