CHAPTER 28: Principles of Radiation Therapy

To effectively incorporate radiation treatment into cancer care, clinicians must understand the fundamental concepts and vocabulary used in radiation oncology. Clinically, radiation therapy, often combined with chemotherapy, can be used as primary treatment for many gynecologic malignancies (Table 28-1). Additionally, radiation therapy may be recommended postoperatively if the probability of tumor recurrence is high. Radiation therapy is also used frequently in the relief of symptoms caused by metastasis of any gynecologic cancer.

Radiation therapy is the focused delivery of energy in tissue to accomplish controlled biologic damage. Radiation used in this therapy can occur as electromagnetic waves or particles.

Electromagnetic Radiation

Photons (x-rays) and gamma rays are the two types of electromagnetic radiation used for radiation therapy. Photons, used in external beam therapy, are produced when a stream of electrons collides with a high atomic number target (tungsten) located in the head of a linear accelerator (Fig. 28-1). In contrast, gamma rays originate from unstable atom nuclei and are emitted during decay of radioactive materials, also termed radionuclides, which are widely used in brachytherapy.

Particle Radiation

Whereas electromagnetic waves are defined by their wavelengths, particles are defined by their masses. For clinical use, particles include electrons, neutrons, protons, helium ions, heavy charged ions, and pi mesons. Except for electrons, which are available in all modern radiation oncology centers, and protons, other particles have limited clinical use. Proton facility numbers are expanding, with 14 facilities operating in the United States and 10 additional centers under construction.

Particles are produced by linear accelerators or other high-energy generators and are usually delivered by external beam. Of clinically used particles, electrons are negatively charged and deposit most of their energy near the surface. In contrast, heavy charged particles, such as protons, deposit most of their energy in the absorbing tissues as their velocity decreases, that is, near the end of the particle path (the Bragg peak effect). Because of this, a major advantage of proton therapy is the lack of an exiting dose through normal tissues. Proton therapy use for gynecologic malignancies is primarily investigational. But as an example, proton therapy can treat affected deep pelvic and paraaortic lymph nodes, while sparing unnecessary dosing and injury to anterolateral organs, such as the bowel and kidneys (Fig. 28-2).

Radiation Sources

Radionuclides

Also called radioisotopes, radionuclides undergo nuclear decay and can emit: (1) positively charged alpha particles, (2) negatively charged beta particles (electrons), and (3) gamma rays. Radionuclides commercially available are shown in Table 28-2. Cesium and iridium are commonly used in gynecologic brachytherapy.

Linear Accelerator

One of the main types of radiation-producing units is the linear accelerator, also called a linac. A linac can produce both photon and electron beams (see Fig. 28-1). In the photon-therapy mode, indicated for deep-seated tumors, the accelerated electron beam is guided to hit a metal target to produce photons. The unit used to describe the energy of a photon beam is MV (million volts). In the electron-therapy mode, indicated for superficial lesions, the electron beam strikes a lead scattering foil instead of the metal target. The unit for electron beam energy is expressed in MeV (million electron volts). Figure 28-3 displays a linac with three moveable components: gantry, treatment head, and couch. These components can all rotate 360 degrees, which allows multiple fields and angles to achieve optimal dose delivery to a tumor.

Electromagnetic Radiation Energy Deposition

When electromagnetic radiation is used in daily clinical practice, it contacts target tissues, and energy is transferred to those tissues. This transfer creates ions by dislodging electrons from atoms within these tissues. These electrons then collide with surrounding molecules to initiate radiation damage.

There are three mechanisms involved in energy transfer: (1) photoelectric effect, (2) Compton effect, and (3) pair production (Fig. 28-4). Depending on the energy level of the incident radiation, one of these mechanisms will predominate. The photoelectric effect is dominant if the incident energy is low (less than 100 kV). The Compton effect dominates in mid- to high energy ranges (1 MV to 20 MV) and is the most important in clinical radiation therapy. Last, pair production occurs when a photon beam with very high energy (beyond 20 MV) strikes the electromagnetic field of the nucleus.

Depth-dose Curve

Controlled biologic damage is accomplished by greater selective radiation dose distribution within malignant tissue than within the surrounding, “innocent bystander” normal tissues. This is achieved by using radiation beams with differing physical properties to define the spatial distribution of an absorbed dose when these beams strike tissue. Ideally, an absorbed radiation dose is as conformal as possible. Perfect conformality is achieved when the targeted malignant tissue absorbs 100 percent of the prescribed dose and the adjacent normal tissues absorb 0 percent. In practice, this cannot be obtained. However, both acute radiation side effects and the potential for late, delayed radiation complications can be minimized as the spatial radiation dose distribution approaches this ideal.

A depth-dose curve specifically illustrates the dose distribution of a given radiation beam as it penetrates tissues. Radiation oncologists rely on these curves when choosing a radiation beam with an appropriate energy to reach a given tumor. With electron beam therapy, the maximum dose lies close to the surface, and therefore, electron beam therapy is indicated for targets that are close to the skin surface, such as metastatic cancer to the inguinal lymph nodes. With high-energy photons, the maximum dose is deposited well below the surface. Beyond this point, the dose gradually tapers as energy is absorbed by the deep surrounding tissues. This explains the so called skin-sparing effect of high-energy photons. A patient with a pelvic malignancy is usually treated with at least 6-MV photon beams.

Dosimetry

This is the discipline of calculating the radiation dose absorbed by the patient. Dosimetric calculations are based on the depth-dose measurements of the radiation beams used to treat an actual patient. The dose distribution is usually displayed as a colorful map overlaid on the radiologic images of the patient. These calculations predict the absorbed dose in a given situation.

Radiation Unit

Quantification of the absorbed radiation dose is essential as it correlates with the biologic effect of radiation. The current Standard International unit for absorbed dose is gray (Gy). One Gy equals 100 rad or 1 joule/kg. Clinically, the radiation doses for curative and palliative treatment are 70 to 85 Gy and 30 to 40 Gy, respectively.

DNA Molecule as Target of Radiation Therapy’s Biologic Effect

The DNA molecule is the target for the biologic effect of radiation on mammalian cells. DNA injuries involve its strands, bases, and cross-links, but the hallmark damage is breaking of single- and most importantly double-stranded DNA. Double-strand breaks lead to DNA fragmentation when two or more breaks are formed and when cells attempt to repair these strand breaks. The DNA pieces may rejoin incorrectly, leading to gene translocation, mutation, or amplification and, ultimately, cell death.

Direct versus Indirect Actions of Ionizing Radiation

Radiation can interact directly or indirectly with the atoms in the DNA molecule. Direct actions create ions that then initiate the biologic damage process. This direct effect is predominant with high linear energy transfer (LET) particles such as protons, fast neutrons, and heavy ions (Fig. 28-5). However, most DNA damage is caused indirectly, which is the predominant effect with low-LET particles such as photons. Indirect DNA damage occurs through an important chemical intermediate, the hydroxyl radical (OH·), which is highly reactive because of its unpaired electron.

Cell Death

The two main cell death pathways after radiation are apoptosis and mitotic catastrophe. Mitotic catastrophe is thought to be the most common mechanism of cell death after radiation exposure. With this, cells with damaged DNA enter mitosis prematurely, before DNA can be repaired, and die attempting to complete the next two to three mitotic cycles. Apoptosis, or programmed cell death, occurs after an intracellular stress, such as radiation-induced irreparable double-strand breaks. A series of events develop rapidly within hours, leading to cell membrane blebbing, apoptotic body formation in the cytoplasm, chromatin condensation, nuclear fragmentation, and DNA laddering (Okada, 2004).

Four R’s of Radiation Biology: Repair, Reassortment, Repopulation, Reoxygenation

In classic radiation biology, there are four mechanisms by which cells respond to radiation. Cellular repair can be described by sublethal damage repair (SLDR) and potentially lethal damage repair (PLDR). SLDR occurs when a radiation dose is split into two or more fractions and a few hours separate the fractions. Cells have time to repair their damage, and their survival rate increases. The last process seen in SLDR is repopulation, which is the tissue’s response to replenish the cell pool (Trott, 1999).

Following the initial repair of sublethal damage, reassortment begins. Within a tumor, proliferating cells are in different phases of the cell cycle (Fig. 27-1). Cells in mitosis (M) and G₂ are most sensitive to radiation. Conversely, cells in G₁ and S (DNA synthesis) phases are less sensitive (Pawlik, 2004). When exposed to radiation, those cells that are in the G₂/M phase are killed. During reassortment, surviving cell populations restart their progression through the mitotic cycle.

The fourth “R” of radiation biology theory is reoxygenation. A tumor cell population is composed of oxygenated and hypoxic components. Cells located within 100 microns of blood capillaries are oxygenated, and beyond 100 microns, cells are hypoxic. After radiation, the oxygenated cells are killed by chemical intermediates described earlier. Following cell death, the tumor shrinks and allows hypoxic cells to be positioned within the oxygen diffusion range of blood capillaries and become oxygenated.

Linear-quadratic Theory and the Alpha/Beta Ratio

For low-LET radiation, the linear-quadratic curve has been adopted to explain the relationship between the fraction of cells surviving a given dose of radiation (Fig. 28-6). The initial linear (alpha) portion of the curve shows that the probability of cell death is proportional to the radiation dose. In the higher-dose region, the curved quadratic (beta) portion indicates that the probability of cell death is proportional to the square of the dose.

The alpha/beta ratio reflects the response of normal tissues to radiation. Early-responding tissues have a high alpha/beta ratio and will manifest reactions to radiation within a few days to weeks after treatment. Examples are tissues with high proliferation rates such as bone marrow, reproductive organs, and gastrointestinal tract mucosa. Preventatively, by administering multiple small radiation dose fractions, there is more sublethal damage repair, and early acute reactions can be decreased.

In contrast, late-responding tissues show clinical reactions only weeks to months after completion of a radiation therapy course. Examples are the lung, kidney, spinal cord, and brain. These tissues have a low alpha/beta ratio and are slow to respond. More time is needed to repair sublethal damage, and thus high-dose per fraction radiation therapy can easily lead to severe late complications.

The expertise of the radiation oncologist who is designing and monitoring a course of radiation treatment is paramount. Radiation oncology is as inherently “operator dependent” as surgical oncology. The radiation oncologist carves out, en-bloc, a volume of cancerous tissue, its local extensions, and its regional lymphatics similar to radical surgical resection, while accommodating the patient’s comorbidities, general health status, and surrounding normal tissue quality.

As cancer management is frequently multimodal, superior treatment outcomes are highly dependent on clear communication between radiation oncologists and their colleagues in surgical and medical oncology. Optimal integration of diagnostic imaging and histologic evaluation is also vital to planning and implementing potentially curative radiation therapy. As such, early involvement of the radiation oncologist in patient evaluation and counseling enhances the probability of effective and coordinated cancer care.

Radiation Fractionation Schemes

Parameters that affect the efficacy and safety of a radiation course include the total radiation dose applied, the size of each radiation “fraction” (treatment), the time between treatments (“fractionation schedule”), and the elapsed time to deliver the total prescribed dose.

Standard Fractionation

Successful eradication of a localized cancer requires that the cancer cells be killed more rapidly and efficiently than surviving cancer cells can proliferate and repopulate. Because of the inevitable exposure of some normal tissues to substantial radiation, there are limits to the total radiation dose that can be prudently administered to a given target volume. In general, delivery of this dose over the shortest feasible elapsed time will maximize efficacy. Accomplishing this objective is limited by the known deleterious consequences of a high dose per fraction on normal tissues. As noted, this can result in delayed radiation injury expressed months or years after therapy completion. For this reason, radiation delivered with curative intent is generally administered in daily treatments (Monday through Friday) of 1.8 Gy to 2.0 Gy. Cumulative doses range from 45 Gy to treat microscopic disease to 70 Gy or more to treat gross disease. This concern for delayed injury is lessened when short courses of radiation are administered with palliative intent, often in dose fractions of 2.5 Gy to 4.0 Gy.

Altered Fractionation

Regimens involving treatments given more than once a day are reserved for selected cases. In such instances, increased local tumor control and decreased long-term complications may be achieved by manipulating both fraction size and overall treatment time. This manipulation leads to a variety of altered fractionations. Two major strategies have been employed, namely, hyperfractionation and accelerated treatment.

With hyperfractionation, the reduction of late damage to normal tissues is sought, and accordingly, a smaller dose per fraction is given. Two or more fractions are administered each day, typically 6 hours apart to provide an interval for normal tissue repair.

Accelerated fractionation entails shortening the treatment duration with or without a decrease in total dose to overcome tumor cell repopulation. The usual weekend break is either shortened or eliminated. With accelerated treatment, however, severe acute reactions are frequent.

Altered fractionation has been studied in gynecologic cancers. Radiation Therapy Oncology Group (RTOG) trials 88-05 and 92-10 were Phase II trials that investigated the use of twice-daily radiation and chemoradiation, respectively, in advanced cervical cancer. RTOG 88-05 showed similar local control, survival rates, and toxicity compared with historical controls. However, when chemotherapy and larger-field twice-daily radiation were added, there were unacceptable rates of late Grade 4 toxicity (Grigsby, 2001, 2002).

Radiation Therapy

External Beam Radiation Therapy

External beam radiation therapy is indicated when an area to be irradiated is large. For example, the fields needed to treat a locally advanced cervical cancer may cover the whole pelvis and occasionally, the paraaortic lymph nodes.

Conformal radiation therapy (CRT) describes a radiation treatment technique that maximizes tumor damage while minimizing injury to the surrounding normal tissues. To this goal, the radiation oncologist must know the precise extent of the cancer to be irradiated and its relationship to surrounding normal tissues. This process begins with a review of the patient’s cancer imaging including computed tomography (CT), magnetic resonance (MR) imaging, and positron emission tomography (PET). Imaging, along with careful review of the patient’s pathology and operative report, assists in defining the 3-dimensional (3-D) target (tumor or regions of potential microscopic tumor spread) and normal tissue volumes.

Next, a simulation is performed in a simulation suite to delineate the anticipated therapy fields prior to an actual treatment session. During this process, patient positioning, immobilization techniques, and treatment fields are defined. If feasible, radiation blocks are also planned to shield normal tissues. The patient is placed in the treatment position, and a CT scan of the area of interest is performed. Later, on each of the computer-based CT scan slices, the radiation oncologist carefully delineates the anatomic areas that will receive a tumoricidal dose. During this, four volumes are defined: (1) a gross tumor volume (GTV), which encompasses any gross disease; (2) a clinical target volume (CTV), which incorporates any areas at risk for microscopic tumor spread; (3) a planning target volume (PTV), which accounts for uncertainties in treatment planning or delivery such as patient motion or daily set-up error; and (4) a volume that defines the normal organs at risk (OAR), which will be exposed, albeit to a lesser radiation dose.

Once simulation is completed, a radiation dosimetrist employs a treatment planning software to develop an optimal plan, called dose optimization. This is often a reiterative process in which the physician and the dosimetrist will arrive at an acceptable option, which means an optimal arrangement of the radiation beams.

One tool that is particularly helpful in the radiation planning and optimization process is the dose volume histogram (DVH). This is a graphic summary of the entire dose distribution to the cancer and normal structures. Thus, the DVH provides information regarding whether the cancer will be adequately treated with a tumoricidal dose and whether surrounding normal structures are minimally affected. In addition to the DVH, dose distributions are displayed as computer-generated radiation dose map images that are overlaid on the CT images (Fig. 28-7). This provides a visual dose-anatomy relationship. These dose distributions are produced for the radiation oncologist to review, adjust, and finally approve. The final chosen plan is reviewed by a radiation physicist who ensures that the physical and technical details can be implemented.

To further improve the conformality of the dose distribution, especially around concave targets, a more advanced 3D-CRT planning system, called intensity-modulated radiation therapy (IMRT), can be used. As a result of this improved conformality, IMRT has the potential to decrease bowel and bladder toxicity during pelvic radiation therapy (Heron, 2003). IMRT modulates the intensity of radiation beams to be used with the help of dedicated computer software. For quality assurance, weekly or sometimes even daily imaging of the treated regions is performed to verify that treatment configurations are correct.

Stereotactic Body Radiation Therapy

Over the past decade, a novel external beam radiation therapy technique, stereotactic body radiation therapy (SBRT), has become commonly used in sites such as the lung, liver, and spine. It uses a hypofractionated regimen of five or fewer fractions (10 to 20 Gy per fraction). Using image-guided radiation therapy (IGRT), precise, safe SBRT has become possible through “real-time” approaches to overcome technical factors such as patient or organ motion and tumor size and shape changes during a treatment course.

Brachytherapy

Brachytherapy means treatment at a short distance. During this therapy, sealed or unsealed radioisotopes are inserted into the cancer or its immediate vicinity. Radiation doses fall sharply with increasing distances from the radioactive source. Thus, brachytherapy is indicated only for small tumor volumes (less than 3 to 4 cm). For this reason, brachytherapy is typically practiced after external beam radiation therapy has decreased a large tumor volume.

Brachytherapy may be intracavitary or interstitial. During intracavitary brachytherapy, applicators that hold sealed radioactive sources such as iridium-192 (¹⁹²Ir) are inserted into a body cavity such as the uterus. Alternatively, interstitial brachytherapy requires the placement of catheters or needles directly into the cancer and surrounding tissues.

Brachytherapy may be temporary or permanent. In temporary brachytherapy, the radioisotopes are removed from the patient after a period of time, ranging from minutes to days. All intracavitary and some interstitial implants are temporary. In permanent brachytherapy, the radioisotopes are left permanently to decay within the tissues.

Equipment

For routine gynecologic intracavitary implantation, standard equipment includes an applicator, called a tandem, which fits into the uterine cavity, and a pair of vaginal applicators, which are known as ovoids (Fig. 28-8). The tandem and ovoid device (T&O) is inserted under general anesthesia or conscious sedation. Following placement, radioactive sources can then be loaded into both the tandem and ovoids. In gynecologic oncology, brachytherapy with T&O is indicated for cervical cancer. For uterine cancer, vaginal brachytherapy with a cylinder is used to treat the vaginal apex or length of the vagina, which is the most common site of disease recurrence after hysterectomy (Fig. 28-9).

For temporary interstitial implantation, flexible plastic catheters or metal needles are surgically placed into the target tissues and held in place by a perineal template. These are then afterloaded with ¹⁹²Ir seeds. Templates are suitable for patients with advanced cancers, suboptimal anatomy for T&O application, and selected recurrent cancers.

In addition to T&O, vaginal cylinder, and interstitial needles, physicians may choose to use a tandem and ring, split-ring, or tandem and cylinder. Appropriate brachytherapy applicator selection requires expertise, as applicator choice depends on patient anatomy and a specific device’s dose distribution.

Manual versus Remote Afterloading

Once the brachytherapy instruments are in place, the radioactive sources are inserted. Historically, the sources were placed manually, however, this method increased hospital staff radiation exposure. Subsequently, a remote afterloading approach was developed and is commonly practiced today. This remote control system delivers a single miniaturized iridium source from a protective safe through connecting cables to the holding devices previously inserted into the patient. Following treatment, the radioactive source is automatically retracted back into the safe.

Low Dose-rate versus High Dose-rate Brachytherapy

Traditionally, low dose-rate (LDR) brachytherapy is delivered over the course of many days and requires patient hospitalization. Over the past few decades, however, high dose-rate (HDR) brachytherapy has become more popular. With this technique, treatment is shortened to minutes. Low dose is defined as dose rates from 0.4 Gy to 2 Gy/hr, and high dose rate as rates higher than 12 Gy/hr. For example, with an intracavitary implant for cervical cancer and an LDR technique, a dose of 30 to 40 Gy is delivered continuously over several days. In contrast, with HDR, an equivalent dose can be delivered in 3 to 5 weekly fractions. The dose per fraction is 5 to 7 Gy and can be given in 10 to 20 minutes. Unlike LDR, HDR avoids lengthy inpatient hospitalization and minimizes patient immobility and thromboembolic events. Furthermore, long-term analysis shows similar local tumor control and late complication rates in patients treated for cervical cancer with both HDR and LDR (Arai, 1991; Hareyama, 2002; Wong, 2003).

Tumor Control Probability

With most epithelial cancers, the probability that radiation therapy will control a cancerous mass depends on the tumor’s size and intrinsic radiosensitivity and on the radiation dose and delivery schedule. For example, within a given stage, large tumors are more difficult to control with radiation than smaller ones (Bentzen, 1996; Dubben, 1998).

Intrinsic Radiosensitivity

It is recognized that a tumor’s radiosensitivity in general is determined by its pathologic type (Table 28-3). However, even cancers with a similar histology may have variable responses to radiation. This may be explained by heterogeneity within a given tumor and by the cancer cell’s ability to repair radiation damage (Schwartz, 1988, 1996; Weichselbaum, 1992).

Treatment Time

When protracted time intervals are required to complete a fractionated radiation therapy course, tumor control probability decreases, especially in rapidly proliferating epithelial cancers. Thus, treatment breaks or delays for any reason are minimized. In a retrospective review of 209 patients with stage I to III cervical cancer treated with radiation therapy, the 5-year pelvic control and overall survival rates were better for those who completed the treatment in less than 55 days (87 percent and 65 percent, respectively) than for those who did so in more than 55 days (72 percent and 54 percent, respectively) (Petereit, 1995).

Tumor Hypoxia

Tumor hypoxia is a major factor leading to poor local tumor control and poor survival rates in patients with cervical cancer (Brizel, 1999; Nordsmark, 1996). The close relationship between tumor hypoxia, anemia, and angiogenesis was demonstrated in a study involving 87 patients with stage II, III, and IV cervical cancer treated with radiation only. Of these, patients with hemoglobin levels <11 g/dL and a median tumor oxygen tension pO₂ < 15 mm Hg had decreased 3-year survival rates (Dunst, 2003).

To overcome tumor hypoxia, many strategies have been devised and vary in efficacy. Of these, hyberbaric oxygen used in conjunction with radiation therapy in cervical cancer was not effective in clinical studies (Dische, 1999). An alternate method to increase oxygen delivery to tissues manipulates blood vessel hemodynamics with either inhaled carbogen (95-percent oxygen and 5-percent carbon dioxide) or nicotinamide (a vasoactive agent). This approach of accelerated radiotherapy with carbogen and nicotinamide (ARCON) improves tumor control in patients with anemia but is not commonly used (Janssens, 2014).

Another approach to minimize tumor hypoxia effects employs bioreductive agents. This family of hypoxic cell sensitizers selectively kills hypoxic cells. Earlier findings with one of these, tirapazamine (TPZ), was encouraging. However, results of a Gynecologic Oncology Group (GOG) phase III trial that evaluated TPZ, cisplatin, and radiation therapy compared with cisplatin and radiation show no improvement in survival or tumor control rates for patients with cervical cancers (DiSilvestro, 2014).

Last, to ensure adequate oxygen carrying capacity, a hemoglobin level of at least 12 g/dL is desirable in patients receiving radiation therapy. To this goal, transfusion ameliorates tumor hypoxia and increases radiation response. In a study of 204 women with cervical cancer who were treated with radiation, those who were transfused to maintain a hemoglobin level >11 g/dL had a similar 5-year disease-free survival rate (71 percent) compared with a group of women who never required transfusion. The disease-free survival rate was only 26 percent for those with persistent anemia (Kapp, 2002). The use of erythropoietin to maintain hemoglobin above 12 g/dL was also tested in a randomized trial of patients with cervical cancer receiving chemotherapy and radiation. This trial closed early due to concerns of increased thromboembolic events with the use of erythropoietin (Thomas, 2008).

Combination of Ionizing Radiation and Chemotherapy

Radiation is often combined with chemotherapy, surgery, or both to increase local disease control and decrease distant metastasis. Radiation therapy and chemotherapy can be administered in a concurrent or alternating fashion to maximize tumoricidal effects and minimize overlapping toxicities and complications (Steel, 1979). This practice is supported by results from many controlled studies involving cervical and other cancers.

In the management of gynecologic cancers, platinum compounds are most commonly used with radiation therapy. Both radiation and cisplatin cause single- and double-strand DNA breaks and base damage. Although most lesions are repaired, if a cisplatin-induced DNA adduct lies close to a radiation-induced single-strand break, then the damage is irreparable and leads to cell death (Amorino, 1999; Begg, 1990). Since the late 1990s, the standard treatment for newly diagnosed locally advanced cervical cancer has been radiation therapy and cisplatin (Keys, 1999; Morris, 1999; Rose, 1999).

Nucleoside analogues such as fludarabine and gemcitabine are also used to enhance the effects of radiation-induced cell killing. These agents inhibit DNA synthesis by blocking cells at the G₁/S checkpoint. The remaining cell population is synchronized at the G₂/M junction, the most radiation-sensitive phase of the cell cycle. Clinically, in a Phase III study of cervical cancer patients, the progression-free survival and overall survival rates improved in patients randomized to receive gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine compared with concurrent cisplatin and radiation alone (Duenãs-González, 2009). However, inclusion of gemcitabine is still considered investigational for cervical cancer treatment.

Taxanes, such as paclitaxel and docetaxel, enhance the effects of radiation by causing microtubule dysfunction and blocking cells at the G₂/M junction (Mason, 1999). Taxanes have been administered with platinum agents and radiation therapy in small nonrandomized trials involving patients with locally advanced cervical cancer (Lee, 2007).

Combination of Radiation Therapy and Surgery

Radiation therapy can be given before, after, or at the time of surgery. With this combination, surgical resection and its associated morbidity can often be minimized. For example, the combination of radiation and surgery in locally advanced vulvovaginal cancer can allow surgeons to avoid extensive surgery such as pelvic exenteration (Boronow, 1982).

Preoperative adjuvant radiation may offer several advantages for tumor control. First, primary cancers tend to locally infiltrate surrounding normal tissues with microscopic extension. Accordingly, radiation can be delivered prior to surgery to decrease the potential for locoregional and distant tumor dissemination and the likelihood of positive surgical margins. To sterilize areas of subclinical infiltration, doses of 40 to 50 Gy administered over 4 to 5 weeks are required. Although preoperative radiation therapy is not expected to render the main tumor mass cancer-free at the time of surgery, it is common to find no evidence of cancer in the surgical specimen. Second, in patients who present with unresectable cancers, preoperative radiation therapy can transform them into suitable candidates for a surgical attempt (Montana, 2000). Surgery is usually delayed 4 to 6 weeks after radiation completion. By then, the acute radiation reactions have subsided, and pathologic interpretation of the resected specimen is easier.

Two studies by the GOG (GOG 71 and 123) have investigated preoperative radiation and chemoradiation, respectively, in patients with bulky stage IB cervical cancer (Keys, 1999, 2003). In both trials, the pathologic complete response rate, defined as no residual disease in a resected specimen, approximated 50 percent.

Postoperatively, a high probability for local recurrence may often be predicted by factors such as positive margins, lymph node metastases, lymphovascular invasion, and high-grade disease. In these cases, postoperative radiation therapy may be beneficial and is ideally delivered 3 to 6 weeks following surgery. This delay allows initial wound healing (Sedlis, 1999). The radiation fields should encompass the operative bed due to the possibility of tumor contamination at the time of surgery and adjacent areas that are at risk for tumor dissemination.

Postoperative radiation is employed in the treatment of many gynecologic malignancies. For cervical cancer, postoperative radiation is recommended in those with lymphovascular invasion, deep stromal invasion, or large tumor size (Sedlis, 1999). Postoperative chemoradiation is offered if positive parametria, positive margins, or positive lymph nodes are found. The addition of cisplatin and 5-fluorouracil to radiation in cervical cancer patients with these high-risk features has been shown to improve survival and tumor control (Peters, 2000).

For uterine cancer, postoperative radiation is frequently used for patients with stage IB or greater disease. Several large randomized controlled trials have demonstrated significant improvements in local control in patients with intermediate-risk endometrial adenocarcinoma who receive adjuvant pelvic radiation (ASTEC/EN.5 Study Group, 2009; Creutzberg, 2011; Keys, 2004). Intermediate risk includes older age, lymphovascular invasion, deep myometrial invasion, or intermediate- or high-grade disease. Patients with fewer risk factors can often be treated with vaginal brachytherapy alone. Vaginal brachytherapy treats the vaginal apex, where approximately 75 percent of recurrences are located. A randomized trial showed similar vaginal and pelvic tumor control rates with fewer side effects when vaginal brachytherapy alone was compared with pelvic external beam radiation therapy (Nout, 2010).

Intraoperative radiation therapy (IORT) is infrequently elected. It may be delivered either by interstitial brachytherapy or by an electron beam produced by a dedicated linear accelerator installed in the operating room. A single dose of 10 to 20 Gy is typically directed to the area at risk for recurrence or suspected of harboring residual cancer (Gemignani, 2001).

Normal Tissue Response to Radiation Therapy

In general, radiation therapy is less well tolerated if: (1) the irradiated tissue volume is large, (2) the radiation dose is high, (3) the dose per fraction is large, and (4) the patient’s age is advanced. Furthermore, the radiation damage to normal tissues can be exacerbated by factors such as prior surgery, concurrent chemotherapy, infection, diabetes mellitus, hypertension, and inflammatory bowel disease.

In general, if tissues with a rapid proliferation rate such as epithelium of the small intestine or oral cavity are irradiated, acute clinical symptoms develop within a few days to weeks. This contrasts with muscular, renal, and neural tissues, which have low proliferation rates and may not display signs of radiation damage for months to years after treatment. To avoid serious complications, radiation oncologists must use published tolerance doses for normal tissues as a guide and rely on their own clinical experience. For example, to avoid severe rectal and bladder complications in patients with cervical cancer, doses of no more than 65 Gy and 70 Gy are recommended to the rectum and bladder, respectively (Milano, 2007).

Epithelium and Parenchyma

Atrophy is the most consistent sequela of radiation therapy. It affects all lining epithelia—including skin and the epithelia of the gastrointestinal, respiratory and genitourinary tracts and of the endocrine glands. Additionally, necrosis and ulceration may develop. Within the submucosa and deep soft tissues, fibrosis frequently follows radiation therapy, leading to tissue contracture and stenosis (Fajardo, 2005).

Of vascular structures, the capillary is the most radiosensitive, and ischemia results from endothelial damage, capillary wall rupture, loss of capillary segments, and reduction of microvascular networks. In large arteries, atheroma-like calcifications develop (Friedlander, 2003; Zidar, 1997).

Skin

Four general types of skin reactions may follow radiation therapy. In order of increasing severity, they include erythema, dry desquamation, moist desquamation, and skin necrosis. For many women during a 6 to 7 week radiation therapy course, the first three of these reactions are common. Within 2 weeks following radiation exposure, the skin develops mild erythema. By the fourth week, the redness becomes more pronounced and dry desquamation may begin. After 5 to 6 weeks, moist desquamation may follow. This involves epidermal sloughing, followed by serum and blood oozing through denuded skin. This reaction is mostly pronounced in skin folds, such as the inguinal, axillary, and inframammary creases.

Preventatively, throughout and after a radiation course, the skin is kept clean and aerated. For dry desquamation, ointments or aloe vera-containing creams promote dermal hydration with an emollient effect. During the moist desquamation phase, skin treatment may include moisturizers (e.g., Biafine), sitz baths, and silver sulfadiazine-containing, nonadhering dressings for weeping areas. Importantly, individuals are instructed to avoid applying heating pads, soaps, or alcohol-based lotions to irradiated skin.

Regeneration of the epithelium starts soon after radiation treatment and is usually complete in 4 to 6 weeks. Months later, areas of skin hyper- and hypopigmentation can be seen. The skin may remain atrophied, thin, and dry, and telangiectasias may be visible.

Vagina

Radiation therapy directed to the pelvis frequently leads to acute vaginal mucositis. Although mucosal ulceration is rare, discharge is present in most cases. For these women, a dilute hydrogen peroxide and water solution used at the vulva provides symptomatic relief.

In contrast to acute changes, delayed reactions to radiation may include atrophic vaginitis, formation of vaginal synechiae or telangiectasia, and most commonly, vaginal stricture. Less frequently, rectovaginal or vesicovaginal fistulas may develop after radiation therapy, especially with advanced-stage cancers. Of these delayed reactions, Grade 3 vaginal stricture is defined by the Common Terminology Criteria for Adverse Events (CTCAE) as “vaginal narrowing and/or shortening interfering with the use of tampons, sexual activity or physical examination” (National Cancer Institute, 2009). Preventatively, vaginal stricture or synechiae may be avoided if intercourse is resumed following treatment or if women are instructed regarding dilator use. Dilators are inserted vaginally by the patient daily for 10 seconds, and this schedule continues from radiation therapy completion until the first follow-up visit at 6 weeks. At this point, weekly insertion or intercourse is recommended. Increased severe late vaginal toxicity is associated with poor dilator compliance, concurrent chemotherapy, and age >50 (Gondi, 2012). Importantly, stricture prevention also aids the ability to complete thorough vaginal examinations for cancer surveillance.

For women who remain sexually active following radiation therapy, water-based lubricants (e.g., Astroglide or K-Y Jelly) may be of benefit during intercourse but have no sustained effects. For chronic vaginal dryness, vaginal moisturizers may prove superior. Moisturizers (e.g., Replens and K-Y Silk-E) can be used daily or several times weekly to maintain moist vaginal tissues. Alternatively, topical estrogen cream (e.g., Premarin cream) may improve atrophic symptoms in those who are estrogen candidates (Table 22-5).

Despite these products, persistent adverse vaginal changes affect sexual dysfunction. In a study of 118 women treated for cervical cancer, 63 percent of those who engaged in sexual activities before radiation therapy continued to do so following treatment, although less frequently (Jensen, 2003). In a comparison of women treated with radiation versus radical hysterectomy and lymph node dissection for cervical cancer, women treated with radiation reported significantly lower sexual dysfunction scores than patients undergoing surgery (Frumovitz, 2005).

Ovary and Pregnancy Outcomes

The effects of radiation on ovarian function depend on radiation dose and patient age. For example, a dose of 4 Gy may sterilize 30 percent of young women, but 100 percent of those older than 40. In addition, fractionated radiation therapy appears to be more damaging. Ash (1980) noted that after 10 Gy given in 1 fraction, 27 percent of the women recovered ovarian function compared with only 10 percent of those receiving 12 Gy over 6 days. In patients with gynecologic cancers who receive pelvic radiation therapy, symptoms of ovarian failure mirror those of natural menopause, and symptom treatment is similar in those who are candidates (Chap. 22).

To minimize radiation exposure to the ovaries of premenopausal women, the gonads may be surgically repositioned, termed transposition, out of the radiation fields. A review of prepubescent and adolescent girls undergoing transposition prior to pelvic radiation demonstrated long-term ovarian preservation rates ranging from 33 to 92 percent. However, only 11 of 347 women (3 percent) achieved pregnancy (Irtan, 2013). Moreover, among female childhood-cancer survivors who received abdominal irradiation, higher spontaneous abortion rates and lower first-born birthweights were observed compared with cancer survivors who were not irradiated (Hawkins, 1989).

Bladder

Most patients receiving pelvic radiation note some acute cystitis symptoms within 2 to 3 weeks of beginning treatment. Although urinary frequency, spasm, and pain develop commonly, hematuria is rare. Typically, phenazopyridine hydrochloride (Pyridium) or fluid ad lib promptly relieves symptoms. Antibiotics are prescribed when indicated. Major chronic complications following radiation therapy are infrequent and include bladder contracture and hematuria. For severe hematuria, bladder saline irrigation, transurethral cystoscopic fulguration, and temporary urinary diversion are proven techniques. Fistulas involving the bladder typically require urinary diversion.

Small Bowel

The small bowel is particularly vulnerable to acute early damage from radiation therapy. After a single dose of 5 to 10 Gy, crypt cells are destroyed, and villi become denuded. An acute malabsorption syndrome ensues to cause nausea, diarrhea, vomiting, and cramping. Adequate fluid intake and a low-lactose, low-fat, and low-fiber diet is recommended. Additionally, antinausea and antidiarrheal medications may be warranted (Tables 25-6, and 42-7). Bowel antispasmodics with sedatives (e.g., Donnatal) are also particularly helpful.

Patients are warned about the late, chronic nature of radiation-induced enteritis. Intermittent diarrhea, crampy abdominal pain, nausea, and vomiting, which in combination may mimic a low-grade bowel obstruction, can develop. Patients are at increased risk if there is comorbidity such as obesity, inflammatory conditions of the pelvis or bowel, prior abdominal surgeries, or small-vessel dis­eases resulting from diabetes or hypertension.

Preventatively, several types of devices have been surgically inserted to displace the small bowel from the pelvis. These have included saline-filled tissue expanders, omental slings, and absorbable mesh (Hoffman, 1998; Martin, 2005; Soper, 1988). Furthermore, defining the areas at risk with surgical clips and careful radiation therapy planning, including the use of IMRT, may minimize bowel toxicity (Portelance, 2001). Consideration of dose constraints can further minimize injury. Studies show that irradiating a volume larger than 15 cm³ or a point dose greater than 55 Gy is associated with a significant risk of small bowel damage (Stanic, 2013; Verma, 2014). Radiation treatment with patients prone can also limit the small bowel dose (Adli, 2003). In contrast, trials incorporating radiation protectors, such as amifostine, have been unsuccessful (Small, 2011).

Rectosigmoid

Commonly, within a few weeks after radiation therapy initiation, patients may develop diarrhea, tenesmus, and mucoid discharge, which can be bloody. In these cases, antidiarrheal medications, low-residue diet, steroid-retention or sucralfate enemas, and hydration are management mainstays. Alternatively, rectal bleeding may be seen months to years after radiation therapy. Hemorrhage can at times be severe and require blood transfusion. Moreover, invasive procedures may be needed to control bleeding neovasculature. These include the topical application of 4-percent formalin, cryotherapy, and vessel coagulation with laser (Kantsevoy, 2003; Konishi, 2005; Smith, 2001; Ventrucci, 2001). During the evaluation of late-onset rectal bleeding, barium enema is often indicated. The study usually reveals narrowing of the rectosigmoid lumen and wall thickening. In cases of severe obstruction, resection of the involved colonic segment is necessary. In addition, rectovaginal fistulas may result from radiation therapy (Chap. 25). Small fistulas may heal over many months following a diverting colostomy.

Brachytherapy, in addition to external beam radiation, can further escalate rectal toxicity. The D2cc metric (minimum dose to the most irradiated contiguous volume of 2 cc) is commonly used to evaluate the rectal dose in brachytherapy and has been associated with increased Grade 2 to 4 rectal toxicities when more than 62 Gy are delivered (Lee, 2012). This metric was developed as part of the GEC-ESTRO (Groupe Européen de Curiethérapie—European Society of Therapeutic Radiation Oncology) guidelines, which provide dose-reporting parameters for the bladder, rectum, and sigmoid colon using 3-D image-based treatment planning (Potter, 2006).

Kidney

Manifestations of acute radiation nephropathy typically appear 6 to 12 months after radiation exposure. Affected patients develop hypertension, edema, anemia, microscopic hematuria, proteinuria, and decreased creatinine clearance (Luxton, 1964). Although deteriorating renal function is occasionally reversible, it usually worsens and leads to chronic nephropathy. Patients receiving concurrent radiation and chemotherapy require special consideration, because of the nephrotoxicity associated with many chemotherapeutics.

Bone

Radiation-induced insufficiency fractures are not infrequent following pelvic radiation. They develop in weakened bone and typically manifest as pain. The sacroiliac joint is most commonly involved (Cooper, 1985). Rates are higher in patients receiving definitive radiation therapy, and in a large series of 557 patients with cervical cancer, 20 percent developed insufficiency fractures over 5 years (Oh, 2008). In a more recent series of 222 patients receiving postoperative pelvic radiation therapy, only 5 percent developed pelvic insufficiency fractures at a median time of 11.5 months after radiation therapy completion (Shih, 2013). The fracture rate was higher in patients with osteoporosis (16 percent), in those on hormone replacement therapy (15 percent), and in patients with a lower body mass index. Treatment for a pelvic insufficiency fracture is conservative and consists of pain management and rest, with most patients becoming symptom free by 20 months.

Hematologic Toxicity

Radiation therapy can significantly deplete bone marrow hematopoietic stem cells that include erythrocyte, leukocyte, and platelet precursors. These effects are exacerbated by combined chemoradiation or by irradiation of large fields that contain a significant portion of bone marrow. Accordingly, there are thresholds at which radiation is held to prevent further bone marrow suppression. For example, if platelet levels measure <35,000 × 10⁹/L and leukocyte counts are <1.0 × 10⁹/L, then radiation may be held until these values rise. For anemia, transfusion is recommended. To spare bone marrow injury, IMRT may be beneficial (Klopp, 2013).

Radiation-induced Carcinogenesis

A secondary cancer may develop as a result of prior radiation therapy. The accepted criteria for the diagnosis of radiation-induced cancer require that the cancer be located within the previously irradiated region and that its pathology differ from that of the original malignancy. Additionally, there should be a latent period of at least a few years. In the updated analysis of the Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC-1) trial, which compared postoperative adjuvant pelvic radiation against observation, the secondary cancer rates at 15 years were 22 percent in the radiation group compared with 16 percent in the observation group. However, this difference did not reach statistical significance (Creutzberg, 2011).

Development of a secondary radiation-induced cancer depends on factors such as patient age at exposure, radiation dose, and susceptibility of specific tissue types to radiation-induced carcinogenesis (Table 28-4). In general, those receiving higher radiation doses and those exposed at an earlier age have increased risks for second malignancies. The latency of secondary tumor development also varies depending on the type of second malignancy. For example, the latent period between radiation exposure and the clinical appearance of leukemia is less than 10 years, whereas solid tumors may not develop for decades. The most common example is development of uterine sarcoma years after pelvic radiation for treatment of cervical cancer (Mark, 1996). Preventatively, irradiation of smaller fields with advanced technologies such as IMRT compared with larger field 2-D external beam radiation may reduce the incidence of radiation-induced malignancies (Herrera, 2014).