General Overview of Radiation Therapy
Ionizing radiation has been used for decades to kill cancer cells. The field of radiation oncology was once known as therapeutic radiology. Megavoltage X-rays are used to penetrate tissues that create double-stranded DNA breaks thereby killing cancer cells. Radiation affects both cancer cells and healthy cells. However, the cancer cells due to mutations do not have the capacity to repair double stranded DNA breaks and therefore die while the healthy cells are able to repair the cellular damage. If the healthy cells are unable to recover from the effect of radiation, then a long term side effect ensues. The goal of radiation oncology is to maximize the therapeutic ratio. The therapeutic ratio is defined as maximum tumor cell killing while respecting normal tissue tolerance levels, that is, minimizing late tissue toxicity or late effects. Sometimes, this is achieved by increasing the total tumor dose while decreasing the dose to the surrounding normal tissues. An example of this would be proton therapy that will be described more later. Another example of being able to increase tumor cell kill without damaging the normal surrounding tissue would be the use of radiosensitizing chemotherapy in addition to radiation therapy. Both of these examples enhance the tumoricidal effect while potentially preserving normal surrounding healthy tissue.
Radiation causes side effects that can be globally classified into two groups: acute side effects and late side effects. Acute side effects are those that come on during the treatment and usually subside within 3 months post treatment. These effects resolve and usually the patient’s function returns to that of baseline. However, radiation can also cause late effects that can happen months to years after the radiation treatment has been delivered. The side effects caused by radiation are strictly determined by the anatomical region being treated. For example, in gynecologic malignancies typically, it is the female pelvis that is being treated with radiation plus or minus the inclusion of lymph nodes within the para-aortic (abdominal) region. For the most part, acute pelvic side effects include bladder changes (frequency, urgency, dysuria, nocturia, and worsening overflow incontinence) as well as rectal changes, including diarrhea, mucus in stools, and hemorrhoidal tissue flare. Most of the side effects are managed conservatively with the use of medications such as Pyridium for dysuria and Imodium for diarrhea. These symptoms will resolve several weeks after the treatment is completed. Late effects due to radiation therapy include changes to the vagina, such as vaginal stenosis, strictures or adhesions, dyspareunia (painful intercourse), vaginal dryness, as well as pelvic floor dysfunction, lymphedema, and ovarian dysfunction.
There are different ways to deliver radiation therapy. The majority of the radiation therapy is performed utilizing external beam radiation therapy as opposed to internal techniques with the utilization of brachytherapy. Typically, external beam is delivered using linear accelerators where X-rays are made by accelerating electrons in a vacuum through a tube which then hit a metal target and turn into photons, or high energy X-rays. This creates the X-ray beam that will be delivered a specific anatomical area in the patient. The majority of radiation oncology facilities use photon energy to treat cancer cells. A minority of facilities are now using proton beam. Protons are positively charged particles that are created in a cyclotron and then diverted into a treatment machine. Proton therapy has the advantage of having no exit dose as opposed to photon energy that has entrance and exit dose. Therefore proton therapy has the added benefit of potentially protecting nearby critical structures in a situation where the area being treated is located in close proximity to a critical structure, for example, spinal cord. Not everybody is a candidate for proton therapy. Proton therapy is also not widely available due to it being cost-prohibitive.
Most of the external beam radiation is delivered utilizing photon energy. Very sophisticated ways of delivering this photon energy are on the market. Modern-day equipment is capable of delivering the radiation beam to within millimeter accuracy. Image-guided radiation therapy uses computed tomography (CT) images to confirm the position of the patient and treatment field to improve the accuracy of treatment. There is also a linear accelerator that is mounted adjacent to an magnetic resonance imaging (MRI) magnet that allows for MRI-guided radiation therapy. This is especially useful when the target is moving or if there is a critical structure within the area being treated that can be identified most accurately with MRI due to better soft tissue delineation. Most facilities use CT-based linear accelerators where CT images are obtained prior to treatment. There are also very accurate and precise treatment delivery systems to treat small tumors to exceptionally high doses. Examples include Gamma Knife for treatment of brain tumors (stereotactic radiosurgery) and CyberKnife for treatment of brain tumors and tumors within the body (stereotactic body radiotherapy).
Another way of delivering a concentrated dose of radiation therapy is with the utilization of brachytherapy. “Brachy” in Greek means close therefore brachytherapy means “close therapy.” Modern-day equipment uses a small but powerful radioactive seed the size of a rice grain, typically Iridium-192. The source is radioactive and undergoes radioactive decay properties. The source is transmitted into a series of applicators that are located inside the patient to deliver a concentrated dose of radiation to a small area. The value of brachytherapy is that it delivers a high dose to a small area that allows us to protect the normal surrounding tissue, thereby enhancing the therapeutic ratio. There are two broad categories of brachytherapy. An intracavitary treatment uses an applicator that is placed within a cavity, such as an applicator that is placed inside the vagina. An example of intracavitary brachytherapy is a vaginal cylinder for the postoperative treatment of endometrial cancer or cervical cancer. A vaginal cylinder is placed inside the vagina in the clinic after which the radioactive seed is transmitted through the inside of the vaginal cylinder that is hollow and thereby treats the top of the vagina to a certain dose. The radioactive seed stays inside the patient as long as necessary to deliver a specific dose (usually less than 10 minutes). This treatment is easy to perform and has very limited morbidity due to its ability to deliver a concentrated dose to within 5 mm of the applicator. A second example of an intracavitary brachytherapy applicator is tandem and ovoid or ring applicator that is used for primary treatment of unresectable cervical cancer. The tandem is a metal applicator that is placed inside the uterus and the ovoids or ring are placed inside the vagina. The units are fastened together and held in position with vaginal packing for definitive treatment of cervical cancer. Typically, these applicators are placed in the operating room with general anesthesia or conscious sedation since the procedure can be uncomfortable especially if the cervix needs to be dilated to accommodate the applicator inside the uterus. Another type of brachytherapy treatment is using interstitial brachytherapy applicators. These are a series of thin long needles that are placed either into the vagina or the paracervical/parametrial tissues to treat either locally advanced vaginal cancer or cervical cancer, respectively. Brachytherapy is an important component of definitive treatment of cervical cancer. Patients who do not receive brachytherapy as a part of their treatment have inferior survival rates. Another example of an interstitial brachytherapy application is the use of radioactive seeds implanted into the prostate for treatment of prostate cancer.
The first step in radiation treatment planning is a targeted CAT scan of the area being treated that is performed in the radiation department. This is called a CT simulation. This scan is utilized to define the target(s) to be treated and the normal tissues to be avoided. Often, the pretreatment diagnostic MRI or positron emission tomography (PET) scan is fused to the planning CT to confidently delineate the area of gross tumor. The treatment plan is then generated with the aid of the dosimetrists and medical physicists. After the plan is approved and quality assurance has taken place by the medical physicists, the patient begins her daily treatment. This includes a series of daily, Monday through Friday, treatments that may take 15–20 minutes daily for up to several weeks. In general, when the pelvis is treated for a gynecologic malignancy, the treatment duration is approximately 5–6 weeks of daily external beam radiation therapy. A brachytherapy treatment may follow the initial pelvic field to boost the dose to the area of concern. The treatment delivery system is painless. The patient lays on the treatment table. The gantry which is the head of the treatment machine that contains the X-ray beam will rotate around the patient to deliver the radiation from multiple angles to treat the designated area in a conformal manner. The radiation only affects the area being treated. Therefore if the patient is having side effects outside of the pelvis, likely the symptoms are due to another cause (e.g., chemotherapy or other comorbid conditions.) The patient is not radioactive during the external beam treatment. The radiation stays within the linear accelerator. The equipment never touches the patient and the patient can resume her daily activities on most occasions. Very frequently the patient will also receive concurrent radiosensitizing chemotherapy. It is known that chemotherapy can enhance the response to radiation therapy, and therefore in certain cases radiosensitizing chemotherapy is used in conjunction with the pelvic radiotherapy to enhance overall survival such as the case with definitive treatment of cervical carcinoma with radiation. In this example the patient will receive chemotherapy once a week through a peripheral vein or a port-a-cath. The infusion takes several hours to perform. The patient will also need to receive her pelvic radiation that day as well. It is common for patients to feel fatigued amongst other side effects during the course of treatment especially since these treatment days can be long.
Typically, a full bladder and an empty rectum are preferred for pelvic treatment of a gynecologic malignancy. There can be significant organ motion due to bladder filling such as is the case in cervical carcinoma. The cervix can move up to 2 cm in superior to inferior direction due to bladder filling. The cervix tumor will also shrink during the treatment, and therefore the treatment plan may need to be adjusted along the way to make sure that the tumor is still being adequately covered within the radiation fields. Prior to each treatment, a quick CT-scan image is obtained on the treatment table in order to ascertain that the radiation is being delivered to the correct area. This on-table, pretreatment CT-scan image is fused with the planning CT-scan image to confirm an exact match. Sometimes, minor modifications have to be made in up to six degrees of freedom. At times, the patient is given feedback to increase bladder filling or conversely decrease rectal filling in order to obtain a better match in position of the internal organs. Obtaining pretreatment imaging is called image-guided radiation therapy that is now being routinely used. This allows us to decrease the amount of radiation exposure to the normal surrounding tissue (bladder, rectum, and bowel). Since we use three-dimensional treatment planning (treatments are based on a pretreatment CT scan image), dose approximations to the normal surrounding organs are known and kept to accepted standards. This helps decrease the chance of causing a severe permanent tissue complication (i.e., small bowel obstruction, perforation, and fistula). The treatment planning process is the most important component of the overall treatment followed by meticulous treatment delivery by trained radiation therapist. The medical physicist is the right hand of the radiation oncologist. The medical physicist verifies the treatment parameters and confirms that the treatment is being delivered as planned. Another important job of the physicist is to make sure that the machines are calibrated correctly. This avoids situations of over or under dosing of patients. The pretreatment daily CT scans that are called cone beam CTs are checked by the physician daily. This allows the physician to confirm that there has been accurate treatment delivery as well as it gives us the ability to assess for tumor response. If there has been significant tumor shrinkage during the treatment, sometimes the patient is replanned (undergoes a new CT simulation) and the treatment is adjusted to its new tumor volume (adaptive replanning.)
The radiation oncologist sees the patient in initial consultation and determines if radiation is appropriate for the patient. If so, the most important question is determining if the patient is curable. In most cases there is significant multidisciplinary interaction between the radiation oncologist, gynecologic oncologist and/or medical oncologist. Rehabilitative physician, ancillary staff, including social workers, nurse navigators, and dietitians, are also important components of the oncology team. When patients receive chemotherapy during the radiation, optimal timing of the two treatments is crucial. If the patient has undergone surgery, the timing and start of adjuvant (postoperative) radiation therapy are critical. Typically, the time frame is 6–8 weeks postoperative if the patient is well healed. In certain cases where there is the possibility of a rapid recurrence such as in head and neck carcinomas, timely initiation of adjuvant treatment is paramount. If there is a long delay between surgery and initiation of treatment, there is the possibility of tumor recurrence. While the patient is undergoing daily treatments, the radiation oncologist sees the patient once-per-week to manage any treatment-related side effects. Once the patient has completed treatment, the patient is seen in follow-up to assess for signs or symptoms of tumor recurrence and for any possible late effects due to radiation therapy. Usually, patients will continue to be seen for ongoing surveillance over the next 5 years.
Most recurrences tend to occur within the first several years of treatment. In gynecologic cancers, initially there is a peak recurrence time of approximately 8 months followed by later recurrence up to 2–3 years posttreatment. Recurrences can be seen even later than this. If there is prompt detection of early recurrence, then there may be a localized treatment that can be offered for salvage such as surgery or a focused stereotactic radiation technique. In more advanced cases a pelvic exenteration that removes all the internal pelvic organs, including the bladder and rectum, may be an option if there is no evidence of metastatic disease. Patients who have human papilloma Virus (HPV)-related disease remain at risk for additional malignancies within the lower genital tract. Therefore a careful history, clinical exam, and complementary diagnostic imaging remain an important part of the overall surveillance.
Managing late radiation effects is an important part of follow-up. Late effects of radiation to the pelvis can include changes to the bladder, rectum, vagina, bowel, skin, and connective tissues, including bone and nerves. These complications tend to occur the first few years posttreatment. Large, locally advanced tumors tend to cause the most side effects due to the volume of radiated tissues. For example, treatment of a large cervical tumor invading the bladder may cause a fistula after the tumor regresses. Radiation cystitis may also occur. This is a small ulceration of the bladder mucosa due to too much radiation to a particular part of the bladder. This is managed with bladder irrigation and catheterization. Occasionally, fulguration is needed to stop the bleeding. Radiation proctitis can be managed with steroid suppositories or argon plasma coagulation. Radiation enteropathy, including obstruction perforation or fistula, is a severe complication of the bowel that occurs when dose is greater than 60 Gy are delivered to the bowel loops. Occasionally, surgical intervention is needed. Duodenal injury may present with bleeding ulceration or stricture formation. Long-term changes to the skin may include fibrosis, telangiectasia, and either hyper or hypopigmentation. In cases where there is a late radiation complication that is not amenable to conservative treatment, hyperbaric oxygen treatments may be useful to help successfully treat radiated tissues. Hyperbaric oxygen helps deliver oxygen to damaged tissues and thereby reverse the late radiation effect.
There are specific late effects due to radiation therapy to the pelvis that may be amenable to rehabilitation. These are discussed in this section.
Vaginal Side Effects
Physical changes to the vagina may include vaginal stenosis, strictures, adhesions, and synechiae. These can make the vagina narrower and shorter. Vaginal synechiae are webs of fibrotic scar tissue that can form after radiation to the vagina. The formation of vaginal synechiae is dose dependent. Synechiae may require disruption using either digital manipulation or manipulation with a dilator. In extreme cases, surgical disruption in the operating room with general anesthesia may be necessary as this can be painful for the patient. In addition, disruption of the scar tissue can cause significant bleeding. Vaginal dilators can be used to treat and prevent vaginal narrowing and scar tissue formation, although the data is inconclusive. A Cochrane Database review by Miles and Johnson concluded that there was no reliable evidence to show that routine dilator use improved late effects of radiation to the vagina. Women who are compliant with dilator use have less late toxicity such as vaginal shortening and stenosis as well as dyspareunia (painful intercourse). We counsel the patient to use the vaginal dilator 10 minutes a day three times per week and to remain sexually active if possible. Discomfort and bleeding is expected and is normal. The dilator should be used long term. If the patient already has significant narrowing, there are graduated vaginal dilator kits that can be used in order to gradually reexpand the vagina.
A common complaint postradiation therapy is dyspareunia. Painful sexual intercourse is related to physical changes of the vagina such as synechiae and vaginal canal shortening due to surgery. It can also be caused by vaginal dryness. There are two components to vaginal moisture. The cervix produces moisture to the top of the vagina and the Bartholin’s glands, that sit at either side of the entrance to the vagina, produce the rest of the lubrication. Many of these patients have undergone a hysterectomy where the cervix is removed. In addition, Bartholin’s glands are extremely sensitive to low radiation doses and lose function after low doses. As a result of radiation therapy, vaginal dryness occurs. In addition, patients who had either their ovaries surgically removed or had the ovaries treated with radiation therapy can also have vaginal dryness due to loss of estrogen production. Supplementation with personal lubricants is extremely important to ease the sexual dysfunction. Occasionally, vaginal estrogen creams can be used with good result. Typically, this is contraindicated in the case of endometrial cancer, since endometrial cancer is estrogen sensitive. Always have the patient consult with her gynecologic oncologist prior to initiation of hormonal creams or other hormonal supplements. Vaginal shortening, due to surgery and/or radiation, can affect the depth of penetration and therefore sexual satisfaction. Unfortunately, there is no way to alter the length of the vaginal canal. Working with a trained vaginal rehabilitation therapist is also useful.
Psychosocial changes also occur. Anxiety over sexual intercourse occurs in both the patient and her partner in most cases. The partner typically worries about hurting the patient, especially if there is postcoital bleeding. Bleeding causes anxiety in the patient as this is the most frequent presenting symptom of both cervical and endometrial cancer. Sexuality counseling is an important component of rehabilitation. Jensen et al published in the International Journal of Radiation Oncology Biology and Physics a longitudinal study of self-reported sexual function and vaginal changes after radiation following treatment for cervical cancer. One hundred and eighteen patients were assessed using a validated self-assessment questionnaire. A percentage of 85 of patients had low or no sexual interest, 35% had moderate-to-severe lack of lubrication, 55% had mild-to-severe dyspareunia, and 30% were dissatisfied with their sexual life. A reduced vaginal dimension was reported in 50% of the patients and 45% were never or only occasionally able to complete sexual intercourse. A greater emphasis needs to be placed on vaginal rehabilitation. A patient is encouraged to work together with their partner as a team in order to restore sexual intimacy.
Ovarian Dysfunction
Extremely low doses of radiation will cause ovarian dysfunction. Doses in the order of 200 cGy will cause severe irreparable and permanent loss of endocrine function of the ovary. This leads to early menopause. Menopausal symptoms include hot flashes, emotional lability, weight gain, decreased libido, and vaginal dryness or atrophy. Estrogen replacement may be considered in certain cases, although it is not usually recommended for endometrial cancers specifically adenocarcinoma that is an especially estrogen-sensitive tumor. For patients who are premenopausal who become menopausal due to treatment but still have a uterus may be candidates for both estrogen and progesterone replacement; low doses up to age 49 may be acceptable. Long-term hormonal supplementation is not indicated. Always consult with the gynecologic oncologist to determine the safety of hormone replacement.
Ovarian transposition also known as oophoropexy is a surgical approach to try to limit the radiation dose to the ovaries. The gynecologic surgeons move the ovaries out of the radiation field in an attempt to preserve ovarian function. The ovaries are typically ligated to the peritoneum as high and lateral as possible. This procedure can be performed laparoscopically with minimal morbidity. Despite moving the ovaries out of the field of radiation, retention of ovarian hormonal function may not occur for multiple reasons. Vascular changes to the ovaries may cause ovarian infarction (i.e., loss of blood supply) and therefore loss of function. Occasionally, the ovaries migrate down into the lower abdomen due to gravity.
For example, a 34-year-old patient was diagnosed with cervical cancer. She underwent a radical hysterectomy and lymph node sampling as well as and ovarian transposition. Her ovaries were secured into her upper lateral abdomen (see Figs. 17.1 and 17.2 ). A dose–volume histogram allows us to see how much dose is to be delivered to a certain volume of a specific organ. In the dose–volume histogram displayed next, the mean doses to the ovaries were less than 200 cGy (right ovary 139 cGy and left ovary 194 cGy) (see Fig. 17.3 ).
