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.
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.
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).
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.
IMRT dose distribution in a patient with stage T4 N2 M0 cancer of the vulva. This technique allows for the delivery of tumoricidal doses to the vulva and inguinal nodes while minimizing that to normal tissues. A. The yellow area displays the actual vulvar cancer and inguinal lymph nodes. Doses to the vulva and femoral heads (F) are shown (arrows). The doses to the vulva and femoral heads are 71.5 Gy and 45 Gy, respectively. B. Pink shading displays the inguinal nodes. Doses to the inguinal nodes, bladder, and rectum are shown (arrows). The doses to the inguinal nodes, bladder, and rectum were 66 Gy, 45 Gy, and 36 Gy, respectively.
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 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.
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).
Typical tandem and ovoids used for cervical cancer brachytherapy. The long slender portion of the device (tandem) is inserted into the endometrial cavity, and white cylinders (ovoids) are positioned in the proximal vagina. Radioactive sources can be loaded into both the tandem and ovoid reservoirs.
Typical cylinder (A) used for vaginal brachytherapy after surgery for uterine cancer. The cylinder is placed in the vagina and high-dose-rate brachytherapy is delivered. This treatment decreases the risk of vaginal cuff recurrences. B. The cylinder comes in different sizes to allow the most appropriate fit for the patient’s anatomy. The largest possible diameter is preferred.
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).
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).
TABLE 28-3Radiosensitivity of Some Selected Cancers ||Download (.pdf) TABLE 28-3 Radiosensitivity of Some Selected Cancers
|Sensitivity ||Cancer Type |
|Highly sensitive ||Lymphoma, dysgerminoma, small cell cancer, embryonal cancer |
|Moderately sensitive ||Squamous carcinoma, adenocarcinoma |
|Poorly sensitive ||Osteosarcoma, glioma, melanoma |
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 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).
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.
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).
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.
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).
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).
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.
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.
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).
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).
TABLE 28-4Susceptibility of Selected Tissues to Radiation-Induced Cancer ||Download (.pdf) TABLE 28-4 Susceptibility of Selected Tissues to Radiation-Induced Cancer
|Susceptibility ||Tissues |
|High ||Bone marrow, female breast, thyroid |
|Moderate ||Bladder, colon, stomach, liver, ovary |
|Low ||Bone, connective tissue, muscle, cervix, uterus, rectum |