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Radiation Therapy for Gynecologic Malignancies
Hematol Oncol Clin N Am 20 (2006) 347–361
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Radiation Therapy for Gynecologic Malignancies Kristin A. Bradley, MDa,*, Daniel G. Petereit, MDa,b a
Department of Human Oncology, University of Wisconsin Medical School, University Hospital & Clinics, K4/B100 Radiotherapy, 600 Highland Avenue, Madison, WI 53792, USA b John T. Vucurevich Cancer Care Institute, Radiation Oncology, Rapid City Regional Hospital, Rapid City, SD, USA
T
he American Cancer Society estimates that in 2005, 660,000 new female cancers will be diagnosed in the United States, and 275,000 women will die of their disease [1]. Of these new cancers, approximately 80,000 will be gynecologic in origin, resulting in an estimated 29,000 deaths [1]. Table 1 compares the 2005 estimates for new cases of gynecologic malignancies with mortality rates for each tumor type. Although tumors of the uterine corpus rank first among new cases of gynecologic malignancies (41,000 new cases in 2005), ovarian cancer has the highest mortality rate at 16,000 [1]. Radiation therapy has long played an important role in the therapeutic management of cancers, including gynecologic malignancies. At the end of the nineteenth century, following the discovery of X-rays by Roentgen in 1895 [2] and the discovery of radium by Marie and Pierre Curie in 1898 [3], the first patient was treated with therapeutic X-rays. During the first few decades of the twentieth century, the use of radiation increased significantly. Some of the earliest uses of therapeutic radiation involved treating gynecologic malignancies, especially uterine tumors. Shortly thereafter, multiple papers were published in Europe and the United States reporting the use of X-rays and radium to treat carcinoma of the uterine cervix [4–7]. In the infancy of therapeutic radiotherapy not much was known or understood about how radiation affects tumor and adjacent normal tissues. As a result, treatment failures and radiation-associated toxicities were frequent. Despite early difficulties, fractionated radiation schedules were quickly developed and became the basis for modern radiation therapy [8]. The importance of brachytherapy was soon recognized as high doses could be delivered while sparing the adjacent normal tissues because of the rapid dose fall off. It became apparent that locally advanced cervical cancer could be cured with brachytherapy, and after 1910, several other anatomic sites were also treated with this modality [9].
* Corresponding author. E-mail address: [email protected] (K.A. Bradley). 0889-8588/06/$ – see front matter doi:10.1016/j.hoc.2006.01.019
© 2006 Elsevier Inc. All rights reserved. hemonc.theclinics.com
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Table 1 2005 Estimates for new gynecologic cancer cases and deaths Cancer origin
Number of new cases
Number of deaths
Uterine corpus Ovarian Cervix Vulva Vagina and others All gynecologic sites
40,880 22,220 10,370 3870 2140 79,480
7310 16,210 3710 870 810 28,910
Data from American Cancer Society. Estimated new cancer cases and deaths by sex for all sites, US, 2005. Available at: http://www.cancer.org. Accessed October 10, 2005.
Over the past 100 years radiation therapy has become an integral treatment modality in the management of various malignancies. For some disease sites its use has decreased in popularity and for others its use has grown dramatically. Currently it is an important therapeutic component in the management of many gynecologic malignancies, including cancer of the uterine cervix, uterine corpus, vulva, and vagina. Although often combined with surgery and chemotherapy, radiation therapy also has a definitive therapeutic role for many cervical, vaginal, and vulvar carcinomas. In this article, the current role of radiation therapy in the treatment of gynecologic malignancies as definitive and adjuvant therapy is reviewed. In addition, the most common radiotherapy techniques used to treat gynecologic cancers and the radiation-related toxicities are discussed. RADIATION THERAPY BASICS Therapeutic radiation can be categorized by the method of production. For example, high-energy machines such as linear accelerators generate external beam radiation through the production of electron beams or X-rays, whereas brachytherapy sources generate gamma ray irradiation through the decay of unstable radioisotopes such as iridium and cesium. Most commonly, radiation therapy involves external beam treatments using X-rays or electrons. The X-rays (photons) and electrons used in radiation oncology are of much higher energy than those used in diagnostic radiology. Most linear accelerators are capable of generating therapeutic X-rays and electrons of various energies. This results in beams with different tissue-penetrating characteristics, making the treatment of malignancies in various anatomic locations possible. In general, higher energy beams are used to treat gynecologic cancers, in which the deeper abdominal and pelvic tissues are the targets. Traditionally, external beam radiotherapy is delivered in multiple daily fractions over several weeks. Dividing the total dose of radiation into multiple smaller fractions spares normal tissue through repair of sublethal damage and repopulation between fractions. In addition, fractionation increases tumor cell kill because reoxygenation and reassortment of cells into sensitive phases of the cell cycle occurs between fractions.
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Although treatment breaks may decrease the acute toxicities of radiation, they may also compromise cervical cancer cure rates owing to the accelerated repopulation of tumor clonogens. With treatment prolongation, surviving tumor cells proliferate more rapidly and become increasingly radioresistant. This phenomenon was shown in a study by Petereit and colleagues [10] in which each additional day of treatment beyond 55 days decreased survival by 1%. The dose-rate is crucial in determining the consequences of a given dose of radiation. Classically, the biologic effect of radiation is reduced as the dose-rate is decreased and the exposure time extended because of the repair of sublethal damage that occurs during prolonged radiation exposure. External beam radiation therapy and high–dose-rate brachytherapy deliver radiation at a dose-rate that does not allow for repair of sublethal damage during the delivery of a given fraction of radiation. To compensate for the loss of sublethal damage repair during treatment, the dose per fraction is lowered to allow for normal tissue repair. INNOVATIONS IN EXTERNAL BEAM RADIATION THERAPY Three-Dimensional Conformal Radiation Therapy Just a few years ago most patients receiving radiation therapy were treated using conventional planning. In this process, a patient undergoes a simulation in which fluoroscopic radiographs are obtained. The physician then outlines the treatment fields to target the tumor while blocking out the normal tissues. Although this technique is still used, most commonly to palliate bone and brain metastases, the majority of radiation oncology facilities use three-dimensional (3-D) conformal radiation therapy (CRT) for planning and treatment delivery. The goal of 3-D CRT is to conform the delivered radiation to the tumor while decreasing the dose to the surrounding normal tissues. To accomplish this, a patient undergoes a planning CT scan with the patient in the treatment position. The CT images are then transferred to a computer equipped with 3-D visualization and planning software. The physician contours the tumor and critical normal structures on every slice. A treatment plan is generated and evaluated by the physician to assess the optimal dose distribution. Intensity-Modulated Radiation Therapy Intensity-modulated radiation therapy (IMRT) is a more specialized 3-D CRT technique used to further minimize the normal tissue dose. Like the 3-D CRT process described above, a planning CT scan is performed and the treatment plan is generated on a computer. IMRT differs from the standard 3-D CRT approach in that the physician defines the target dose and then establishes dose constraints or limits for normal structures. Once this is done, an optimal treatment plan is generated by way of computer algorithms that modulate the intensity of the radiation beams. This process creates a large number of sub-beams with varying radiation intensity, resulting in steep dose gradients between the tumor and adjacent structures. IMRT has the potential to widen the therapeutic window either by dose escalation with higher biochemical control rates as in
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prostate cancer or by conformal avoidance to reduce complications such as xerostomia for head and neck cancers. IMRT increasingly is being investigated for gynecologic cancers either to reduce the small bowel or bone marrow dose or to dose escalate the pelvic or para-aortic lymph nodes [11–14]. Mundt and colleagues [14] reported a significant reduction in dose to the bone marrow with IMRT compared with standard pelvic radiotherapy. Patient and organ motion remain major constraints that prevent wider implementation of this technology, as documented in a recent study by Ahamad and coworkers at the M.D. Anderson Cancer Center [11]. Until these issues of pelvic organ motion and reproducibility of patient positioning are resolved, IMRT for gynecologic malignancies may not become as commonplace as IMRT for cancers of other anatomic sites. BRACHYTHERAPY Brachytherapy, or radiation delivered at a close distance, is a widely used technique that has been in existence for more than a century. It is used either alone or in conjunction with external beam radiotherapy to treat various cancers. It consists of placing radioactive sources close to or in contact with the tumor. Treatments vary depending on the dose-rate, mode of surgical implantation, and whether the brachytherapy implant is permanent or temporary. In the past, most brachytherapy treatments were low–dose-rate (LDR), but high– dose-rate (HDR) brachytherapy use has increased dramatically in the past several years because treatments are delivered in a few minutes, thereby permitting outpatient therapy. In addition, the computer-controlled remote afterloading device eliminates radiation exposure to the physician and the nursing staff. LDR techniques were developed in an era when remote afterloading technology was unavailable, and remote afterloading techniques were developed because of concerns about radiation exposure to health care workers. For many years, available technology only allowed brachytherapy treatments for short duration, and it was therefore necessary to deliver remote afterloading brachytherapy at high dose-rates [15]. In more recent years, new technology has allowed remote afterloading brachytherapy to be given at low dose-rates as well. Even though biologic advantages for LDR are claimed, there are additional advantages for HDR brachytherapy, including rigid immobilization, outpatient treatment, patient convenience, and potential cost savings [16–18]. Brachytherapy, although now used in radiation therapy to treat many different tumor types, has long played a role in the treatment of gynecologic malignancies. It remains an essential component in the definitive treatment of cervical carcinoma with radiation therapy. CERVICAL CANCER Although the incidence of cervical carcinoma in the United States has declined over the last few decades because of the widespread use of Papanicolaou screening, cervical cancer remains one of the leading cancer killers of women worldwide. Treatment of cervical carcinoma depends on the stage at diagnosis. The International Federation of Gynecology and Obstetrics (FIGO) clinical staging
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system is used. It allows for basic evaluations and studies to stage the patient’s disease, but does not incorporate information gained from modern imaging such as CT, MRI, or positron emission tomography (PET). By excluding the findings from these radiographic studies one can compare outcomes for patients treated across the world, including nations where cervical cancer is common but the availability and use of these imaging modalities is not. Positive findings from CT, MRI, or PET scans do not change the patient’s stage, but do influence the prognosis and may alter treatment decisions. CT is useful for identifying hydronephrosis and enlarged pelvic and para-aortic lymph nodes; MRI is used to identify parametrial extension and rectal or bladder invasion; and PET has been shown to be more sensitive than CT for detection of nodal disease and distant metastasis [19,20]. A study by Grigsby and colleagues [20] highlighted the impact of PET and the poor prognosis conferred by lymph node positivity. In this study, 2-year progression-free survival according to CT and PET findings for pelvic lymph nodes was 73% if CT and PET negative, 49% if CT negative but PET positive, and 39% if CT and PET positive, P = .001. Patients who had para-aortic lymphadenopathy had a worse outcome with 2-year progression-free survivals of 64% if CT and PET negative, 18% if CT negative but PET positive, and 14% if CT and PET positive, P < .001. Because of the impact lymph node metastasis has on survival, the use of PET is increasing to assist with treatment planning and to counsel patients about their overall prognosis [21]. In January 2005, the Centers for Medicare and Medicaid Services approved the use of 18F-2-deoxy-2-fluoro-D-glucose PET (18F-FDG-PET) imaging for the initial staging of cervical carcinoma [22]. Treatment for cervical cancer depends primarily on the stage of disease. Table 2 summarizes treatment options and outcomes by stage. For early microinvasive cervical carcinoma (FIGO IA1), options include a simple hysterectomy or radiotherapy. In larger microinvasive tumors (IA2 or IB1 disease), a radical hysterectomy with a pelvic lymphadenectomy or definitive radiotherapy achieves equivalent local control and survival [23,24]. Radical surgery may be used to treat patients who have stage IB2 and IIA disease, but because of
Table 2 Treatment options and outcome for cervical carcinoma by International Federation of Gynecology and Obstetrics stage FIGO stage
Treatment options
5-y overall survival (%)
IA1 IA1, IA2 IB1 IB2, IIA IIB III IVA IVB
Simple hysterectomy, radiation therapy Radical hysterectomy, radiation therapy Radical hysterectomy, radiation therapy Chemoradiation therapy, radical hysterectomy Chemoradiation therapy Chemoradiation therapy Chemoradiation therapy, exenteration Palliation
>95 >95 80–90 80 65–75 30–50 10–20 <5
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the frequent need for postoperative radiation therapy based on surgical pathologic findings, many institutions recommend definitive radiation therapy in an attempt to avoid the combined toxicities of surgery and radiation. For more advanced stages (FIGO IB2 to IVA), definitive radiation therapy has been used successfully to treat cervical cancer for nearly a century. Standard therapy consists of carefully planned, high energy external beam radiotherapy combined with brachytherapy, either LDR or HDR. Using radiation alone, cure rates as high as 50% to 90% for patients who have stage IB to IIIB disease can be achieved [25–27]. Traditionally, definitive radiotherapy alone has been the standard of care for treating cervical carcinoma. In 1999, the National Cancer Institute (NCI) issued an alert that chemotherapy should be added to primary radiation therapy for cervical cancer. This alert was based on data from five cooperative grouprandomized trials that showed an overall survival advantage for cisplatinbased chemoradiation therapy compared with radiation therapy alone [28–32]. The studies included either FIGO stage IB2 to IVA patients treated with primary radiation therapy or stage I to IIA patients treated with primary surgery and found to have positive lymph nodes, parametrial extension, or positive surgical margins. The chemotherapy regimens that were used varied, but were all cisplatin based. The relative survival improvements demonstrated by these trials were 30% to 50%, with an average absolute survival benefit of 10%. The NCI Canadian study did not show a benefit with the addition of chemotherapy to radiation [33]. The investigators postulated that a survival benefit was not observed with the addition of chemotherapy because optimal radiation parameters were achieved, such as avoidance of treatment prolongation (radiation was completed in 7 weeks) and minimization of anemia (hemoglobin levels were maintained at 11 g/dL). Because most of the published randomized data support the use of concurrent chemotherapy, it is considered standard therapy for patients who have stages IB2 or higher or in the postoperative setting with positive nodes, parametria, or surgical margins. Off study, the most common chemotherapy regimen consists of cisplatin alone at 40 mg/m2/wk for 5 to 6 weeks concurrent with radiation. Definitive radiotherapy for cervical cancer includes both external and internal radiation modalities. External beam radiation therapy is directed daily to the pelvis and sometimes to an extended field that includes the retroperitoneal lymph nodes over 5 to 6 weeks. Typical doses to the whole pelvis are 45 to 50.4 Gy at 1.8 to 2 Gy/fraction with fields designed to encompass the primary cervical disease, any parametrial or vaginal extension, and the lymph node chains at risk, including the hypogastrics and external iliacs. Known parametrial disease or positive nodes are then “boosted” to a higher dose, ranging from 50.4 to 60 Gy. Most commonly, the radiation fields are designed using 3-D, CT-based planning that allows for visualization of the cervix, bladder, vessels, lymph nodes, and other anatomic structures. As mentioned earlier, MRI and PET findings do not change the stage of the tumor, but can be used to assist with radiation treatment planning. Generally, there are either two or
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Fig. 1. Tandem and ovoids applicator used for high–dose-rate brachytherapy for cervical cancer.
four radiation fields, coming in from anterior, posterior, right lateral, and left lateral directions. IMRT is currently under investigation to determine if toxicities can be decreased by reducing doses to the adjacent normal tissues and if higher doses can be safely administered to lymph nodes containing metastatic disease [11–14]. Brachytherapy, or internal radiation, is a crucial part of potentially curing advanced cervical carcinoma because high doses can be delivered to the tumor while sparing the bladder and rectum because of the rapid dose fall off. The choice of brachytherapy, either LDR or HDR, is usually institution driven with HDR increasing in popularity for reasons previously discussed. Different radioisotopes are used in brachytherapy and are chosen based on their unique combination of properties including energy, half-life, physical size, and safety issues. For gynecologic malignancies, either Iridium-192 or Cesium-137 is used for LDR, and Iridium-192 is used for HDR in the United States. Brachytherapy is delivered using various techniques and applicators. Brachytherapy for cervical carcinoma uses an intrauterine applicator, called a tandem, and either vaginal ovoids (Figs. 1 and 2), vaginal cylinders, or a vaginal ring. LDR usually requires one to two insertions, whereas HDR requires three to five.
Fig. 2. Lateral fluoroscopic image of tandem and ovoids in a patient with cervical cancer.
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With either method of dose-rate delivery, brachytherapy is initiated at some point during external beam radiation once optimal tumor reduction is achieved, that is, tumor size less than 4 cm. Depending on the tumor size, 2 to 5 weeks of external beam radiation may be necessary before adequate cervical regression occurs. Because LDR brachytherapy requires one to two insertions, this can be delivered near the end of or after completion of external beam radiation, whereas HDR insertions begin sooner to minimize the overall treatment duration. It is common to perform two HDR fractions per week as external beam treatments continue on the other days of the week. Patients do not receive both external beam and brachytherapy on the same day. Intravenous conscious sedation is administered during each procedure for patient comfort. On occasion, a spinal or general anesthetic is necessary. The total dose prescribed to the paracervical tissues (Point A) is in the range of 80 to 85 Gy when using LDR. With HDR, the total dose is lower because of the dose-rate effect. Comparable biologically effective doses are prescribed in both systems, however. It is critical that the total doses to the bladder, rectum, and sigmoid remain below a certain level to minimize complication rates. Three randomized trials and several single institutional experiences have documented the equivalency of HDR to LDR [34–36]. ENDOMETRIAL CANCER Endometrial cancer is the most common gynecologic malignancy, with an estimated 41,000 cases in 2005. Standard treatment consists of an extrafascial hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and an assessment of the pelvic and para-aortic lymph nodes. Fortunately, because of the presence of early symptoms such as vaginal bleeding, most patients are diagnosed at an early stage. The need for adjuvant postsurgical therapy depends on surgical and pathologic findings. For stage I patients who have uterine-confined disease, the indications for adjuvant radiation therapy continue to evolve and are based on the patterns and risk for recurrence in addition to the efficacy of additional treatment. The assessment of risk depends on the depth of myometrial invasion, tumor grade, lymphovascular space invasion (LVI), and degree of surgical staging of the lymph nodes. When a staging lymphadenectomy has not been performed or is incomplete, the findings of Gynecologic Oncology Group (GOG) #33 are helpful in estimating the risk for pelvic nodal involvement and recurrence [37,38]. Adjuvant radiation options include pelvic radiotherapy, vaginal cuff brachytherapy, or a combination of both. Pelvic radiation therapy is recommended for patients whose lymph nodes have not been surgically evaluated and who have a significant risk for microscopic spread to the nodes based on the depth of invasion and tumor grade. In general, these are patients who have deeply invasive tumors (stage IC) with intermediate- to high-grade disease (grade 2–3). Two randomized trials investigating the efficacy of pelvic radiotherapy have been published [39,40]. GOG #99 randomized patients after complete surgical staging to either observation or pelvic radiotherapy [40]. Most patients had well or moderately differentiated tumors (80% grade 1–2) that invaded one half or
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less into the myometrial wall (60% stage IB). Pelvic radiation therapy decreased recurrences at 2 years (12% observation versus 3% pelvic radiation, P = .007), but did not impact survival at 4 years (86% observation versus 92% radiation, P = .557). Additional analysis demonstrated an unfavorable group with highrisk features (approximately one third of the patients) who accounted for two thirds of the recurrences. High-risk features included outer third myometrial invasion, grade 2–3 disease, and the presence of lymphovascular space invasion. For women 50 years of age or older with two high-risk features, or women 70 years of age or older with one high-risk feature, the 2-year cumulative incidence of recurrence was 26% without pelvic radiation and 6% with radiation. In these well staged patients who had surgical lymph node staging, the most common site of preventable failure was the vaginal apex. The isolated vaginal cuff recurrence rate was 0.5% for those irradiated and 7.8% for those who were not. There was no statistically significant difference in the small bowel obstruction rate between the treatment arms; however, six of the seven patients who developed a grade 3 or 4 obstruction received pelvic radiotherapy. A European randomized trial also compared pelvic radiotherapy to observation after surgery for a similar patient cohort [39]. Unlike GOG #99, however, this study did not permit staging lymphadenectomies. Local–regional recurrences were reduced from 14% to 4% with the addition of pelvic radiotherapy (P < .001), with nearly 75% of the recurrences at the vaginal cuff. Survival was not significantly different between the observation and pelvic radiation groups as the 5-year actuarial survival was 81% in the radiotherapy group and 85% in the control group (P = .31). Patients who received adjuvant radiotherapy experienced a 2% significant complication rate, primarily enteric, versus 0.3% in the observation group. Vaginal cuff brachytherapy is a cost-effective, low-morbidity alternative to external beam radiotherapy that treats the site of greatest risk for recurrence in many patients. Because the vagina is the most common site of failure and external beam radiotherapy is associated with a significant small bowel obstruction rate of up to 10% for completely staged patients, vaginal cuff brachytherapy alone is often recommended for both low- and intermediate-risk stage I endometrial patients. Brachytherapy alone also has been used for highrisk stage I patients after a lymphadenectomy; however, failure patterns tend to be more distant than with pelvic radiotherapy [41–43]. Vaginal cuff brachytherapy has significantly less toxicity and affords nearly the same protection against recurrences as pelvic radiotherapy [44–46]. Vaginal cuff brachytherapy generally is delivered in three or four outpatient visits using HDR Iridium-192, whereas pelvic radiation therapy requires 5 to 6 weeks of daily treatment. The decision to recommend pelvic radiation versus vaginal cuff brachytherapy continues to evolve and varies among gynecologic and radiation oncologists. The investigators’ recommendations for pelvic radiation or vaginal cuff brachytherapy for stage I patients are detailed in Table 3. With short follow-up, GOG #99 and the European postoperative study (PORTEC) reported high salvage rates of approximately 80% for isolated vagi-
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Table 3 Suggested guidelines for adjuvant radiation therapy for stage I endometrial cancer with adequate lymphadenectomy FIGO stage
Grade 1
Grade 2
Grade 3
IA (no myometrial invasion) IB ( ≤ 50% myometrial invasion) IC ( ≥ 50% myometrial invasion)
None
None
Vaginal cuff brachytherapy
None
Vaginal cuff brachytherapy Pelvic radiation
Vaginal cuff brachytherapy or pelvic radiationa Pelvic radiation
a
Vaginal cuff brachytherapy or pelvic radiationa
If lymphovascular space invasion or suboptimal lymphadenectomy, favor pelvic radiation therapy.
nal cuff recurrences [39,40]. Data from the M.D. Anderson Cancer Center suggest that these initially high salvage rates are not durable with longer follow-up [47]. Although the 2-year pelvic control and survival rates were encouraging (82% and 75%), these rates dropped to 69% and 43%, respectively, at 5 years. This further reduction in survival at 5 years was because of the development of metastatic disease. This drop in survival at 5 years is critical because the data at 2 years is comparable to the results at 2 years in both the PORTEC and GOG trials. With longer follow-up, it is anticipated that these high salvage rates will not be durable. Therefore the necessity of preventing vaginal recurrences with adjuvant radiotherapy is crucial. For stage II endometrial cancer with involvement of the cervix, the choice of pelvic irradiation or vaginal cuff brachytherapy alone depends on the depth of myometrial invasion, tumor grade, adequacy of lymphadenectomy, and the extent of cervical invasion. With cervical stromal invasion (stage IIB), a combination of pelvic radiation and vaginal cuff brachytherapy is usually recommended. Until recently, adjuvant radiation was commonly used for stage III–IV nonmetastatic endometrial cancer. With the results of GOG #122, there has been an increase in the use of chemotherapy and a decrease in the use of radiation therapy [48]. This phase III study randomized nonmetastatic stage III–IV patients to whole abdominal radiotherapy (WAR) with a pelvic boost, or platinum-doxorubicin chemotherapy. The patients in the chemotherapy arm had superior progression-free survival (59% versus 46% at 2 years, P < .01) and overall survival (70% versus 59% at 2 years, P < .01) compared with the patients in the radiation arm. Unfortunately, approximately 55% of the patients who had advanced endometrial cancer still had recurrence. Many of the patients who underwent WAR in GOG #122 were not ideal radiation candidates in that they had bulky disease above the pelvis. WAR is typically only recommended if there is microscopic disease above the pelvis. Current efforts integrating both effective systemic therapies and radiation therapy to high-risk areas, that is, pelvic radiotherapy or brachytherapy, will most likely be needed to optimize cure rates.
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VULVAR CANCER The incidence of vulvar and vaginal cancer in the United States is considerably lower than that of other gynecologic malignancies. The role of radiation therapy in the management of these two diseases, however, is considerable. For early stage vulvar cancer (T1–T2), surgery with a radical wide local excision and inguinal lymph node dissection is the preferred treatment. The indications for postoperative radiation therapy are positive surgical margins, margin less than 8 mm, two or more inguinal lymph nodes positive, a grossly positive lymph node, or extracapsular nodal extension. Adjuvant radiation is sometimes considered for tumors that do not meet the above criteria but are deeply invasive and have lymphovascular space invasion. The rationale for treating patients who have close or positive margins comes from a study by Heaps and colleagues [49] in which the local recurrence rate was 48% if the margin was less than 8 mm compared with 0% if the margin was 8 mm or greater, P < .001. Of the patients who had margins less than 8 mm, half were observed after surgery and the other half received adjuvant radiation therapy to the vulva. The patients receiving radiation had lower local recurrence rates and improved survival compared with the patients who did not receive radiation. The GOG reported results of a randomized trial in which patients who underwent a radical vulvectomy and bilateral groin node dissection were randomized to a pelvic lymph node dissection or pelvic and inguinal radiation therapy if the inguinal lymph nodes were pathologically positive intraoperatively [50]. The study closed early when an interim analysis showed a statistically significant survival advantage for the radiation arm: 2-year survival rate of 68% for the radiation group compared with 54% for the pelvic node dissection group (P = .03). The advantage was most dramatic for patients who had a grossly positive node or two or more positive inguinal lymph nodes. There was no significant difference in survival for patients who had one microscopically positive node. In the postsurgical setting, radiation can be directed to the pelvis and groins, the vulva alone, or the primary site and draining locoregional lymphatics, depending on the risk factors for local recurrence and metastatic lymph node spread. Typical adjuvant doses are 45 to 50 Gy delivered over 5 to 5.5 weeks of daily treatment. Various radiation techniques are used to ensure adequate coverage of the target tissues. For more advanced vulvar cancer that involves or is adjacent to the anus, clitoris, or urethra, the recent trend has been toward neoadjuvant or primary chemoradiation to avoid exenteration and permit a less radical and debilitating surgery. There have been numerous small studies investigating this approach, but no randomized trials have been published. Based on the success of these smaller, single-institution studies, the GOG is currently conducting a phase II study of chemoradiation for locally advanced vulvar carcinoma [51–54]. In the open GOG study, radiation is delivered to the primary tumor, pelvis, and inguinal regions to 45 Gy followed by a boost to the primary tumor to 57.6 Gy, all delivered with concurrent weekly cisplatin. After 6 to 8 weeks, response to
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chemoradiation is assessed. Patients who have a partial response undergo resection of the residual disease. VAGINAL CANCER Radiation therapy is usually the treatment of choice for all stages of vaginal cancer to avoid exenterative surgery and potentially preserve sexual function. The exception is stage I disease involving the upper one third of the vagina where a radical hysterectomy may be considered. Selected patients who have limited, superficial disease can be treated with intracavitary vaginal brachytherapy alone, but most patients receive a combination of external beam radiation therapy and brachytherapy. Interstitial brachytherapy using intraoperative needle placement is recommended for thicker, more extensive tumors to deliver adequate dose to the vagina and paravaginal tissues. Based on the benefit of adding chemotherapy to radiation therapy for cervical cancer, concurrent cisplatin-based chemoradiation therapy has been used to treat vaginal cancer as well. This extrapolation from cervical cancer to vaginal cancer is reasonable, as a randomized trial of radiation versus chemoradiation is unlikely to be undertaken for vaginal cancer because of its infrequency. OVARIAN CANCER Radiation therapy plays a limited role in the management of ovarian carcinoma. Patients undergo a staging laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and assessment of the pelvic and para-aortic lymph nodes. After optimal surgical cytoreduction, adjuvant chemotherapy is recommended for most patients. In the past, whole abdominal radiation or intraperitoneal radiocolloid ( 32P ) instillation were used to treat the entire peritoneal cavity that is at risk. Because of the increased risk for late bowel complications associated with postoperative radiation, chemotherapy has eclipsed radiation therapy as the standard adjuvant therapy [55]. External beam radiation still has an important and effective role in the palliation of symptomatic recurrences. Approximately 50% to 75% of patients experience significant symptomatic relief from a short course of external beam radiation [56]. SUMMARY In the last century, radiation has been successfully used as primary and adjuvant treatment in the management of gynecologic malignancies. It is anticipated that radiation will continue as an integral component in the treatment of cervical, endometrial, vulvar, and vaginal carcinoma. Current efforts are directed at improving control rates while minimizing treatment-related toxicities through the use of more conformal external beam radiotherapy techniques, refinement of brachytherapy techniques, and the integration of chemotherapy. References [1] American Cancer Society. Estimated new cancer cases and deaths by sex for all sites, US, 2005. Available at: http://www.cancer.org. Accessed October 10, 2005. [2] Roentgen WC. On a new kind of rays (preliminary communication). Translation of a paper
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[13]
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read before the Physikalische-medicinischen Gesellschaft of Wurzburg on December 28, 1895. Br J Radiol 1931;4:32. Curie P, Curie M, Bemont G. Surune nouvelle substance fortemont radioactive contenue dans la pechblende (presented by M. Becquerel). Compt Rend Acad Sci (Paris) 1898;127:1212–7. Cleaves MA. Radium: with a preliminary note on radium rays in the treatment of cancer. Med Rec 1903;64:601–6. Janeway HH. The treatment of uterine cancer by radium. Surg Gynecol Obstet 1919;29:242. Morton WJ. Treatment of cancer by the x-ray, with remarks on the use of radium. Int J Surg 1903;14:289–300. Degrais P. Radium therapie du cancer du col de l'uterus. Surg Gynecol Obstet 1915; 22:298. Coutard H. Principles of x-ray therapy of malignant diseases. Lancet 1934;2:1–8. Brady LW, Kramer S, Levitt SH, et al. Radiation oncology: contributions of the United States in the last years of the 20th century. Radiology 2001;219:1–5. Petereit DG, Sarkaria JN, Hartmann TJ, et al. The adverse effect of treatment prolongation in cervical carcinoma. Int J Radiat Oncol Biol Phys 1995;32:1301–7. Ahamad A, D'Souza W, Salehpour M, et al. Intensity-modulated radiation therapy after hysterectomy: comparison with conventional treatment and sensitivity of the normal-tissuesparing effect to margin size. Int J Radiat Oncol Biol Phys 2005;62:1117–24. Guerrero M, Li XA, Ma L, et al. Simultaneous integrated intensity-modulated radiotherapy boost for locally advanced gynecological cancer: radiobiological and dosimetric considerations. Int J Radiat Oncol Biol Phys 2005;62:933–9. Ahmed RS, Kim RY, Duan J, et al. IMRT dose escalation for positive para-aortic lymph nodes in patients with locally advanced cervical cancer while reducing dose to bone marrow and other organs at risk. Int J Radiat Oncol Biol Phys 2004;60:505–12. Lujan AE, Mundt AJ, Yamada SD, et al. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516–21. Wakabayashi M, Irie G, Sugawara T, et al. The trial production of remote afterloading system unit. Jpn J Clin Radiol 1966;11:678–84. Bastin K, Buchler D, Stitt J, et al. Resource utilization. High dose rate versus low dose rate brachytherapy for gynecologic cancer. Am J Clin Oncol 1993;16:256–63. Stitt JA, Fowler JF, Thomadsen BR, et al. High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system: I. Clinical and radiobiological considerations. Int J Radiat Oncol Biol Phys 1992;24:335–48. Wright J, Jones G, Whelan T, et al. Patient preference for high- or low-dose-rate brachytherapy in carcinoma of the cervix. Radiother Oncol 1994;33:187–94. Rose PG, Adler LP, Rodriguez M, et al. Positron emission tomography for evaluating paraaortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17:41–5. Grigsby PW, Siegel BA, Dehdashti F. Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 2001;19:3745–9. Havrilesky LJ, Kulasingam SL, Matchar DB, et al. FDG-PET for management of cervical and ovarian cancer. Gynecol Oncol 2005;97:183–91. Centers for Medicare & Medicaid Services. Expanded coverage for PET scans for cervical and other cancers, new coding for PET scans, and billing requirements for PET scans for specific indications of cervical and other cancers. Available at: http://www.cms.hhs.gov. Accessed October 10, 2005. Newton M. Radical hysterectomy or radiotherapy for stage I cervical cancer. Am J Obstet Gynecol 1975;123:535–42. Landoni F, Maneo A, Colombo A, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997;350:535–40. Fletcher G. Adenocarcinoma of the uterus. In: Textbook of Radiotherapy. 3rd edition. Philadelphia: Lea & Febiger; 1980. p. 789–808.
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[26] Horiot JC, Pigneux J, Pourquier H, et al. Radiotherapy alone in carcinoma of the intact uterine cervix according to G. H. Fletcher guidelines: a French cooperative study of 1383 cases. Int J Radiat Oncol Biol Phys 1988;14:605–11. [27] Perez CA, Camel HM, Kuske RR, et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix: a 20-year experience. Gynecol Oncol 1986;23: 127–40. [28] Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 1999;340:1144–53. [29] Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340:1137–43. [30] Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154–61. [31] Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 1999;17:1339–48. [32] Peters 3rd WA, Liu PY, Barrett RJ, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606–13. [33] Pearcey R, Brundage M, Drouin P, et al. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 2002;20:966–72. [34] Petereit DG, Sarkaria JN, Potter DM, et al. High-dose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence–the University of Wisconsin experience. Int J Radiat Oncol Biol Phys 1999;45:1267–74. [35] Sarkaria JN, Petereit DG, Hartmann TJ, et al. A comparison of the efficacy and complication rates of low dose rate versus high dose rate brachytherapy in the treatment of uterine cervical carcinoma. Int J Radiat Oncol Biol Phys 1994;30:75–82. [36] Hareyama M, Sakata K, Oouchi A, et al. High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 2002;94:117–24. [37] Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study. Cancer 1987;60:2035–41. [38] Morrow CP, Bundy BN, Kurman RJ, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65. [39] Creutzberg CL, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. Lancet 2000;355:1404–11. [40] Keys HM, Roberts JA, Brunetto VL, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004;92:744–51. [41] Chadha M, Nanavati PJ, Liu P, et al. Patterns of failure in endometrial carcinoma stage IB grade 3 and IC patients treated with postoperative vaginal vault brachytherapy. Gynecol Oncol 1999;75:103–7. [42] Anderson JM, Stea B, Hallum AV, et al. High-dose-rate postoperative vaginal cuff irradiation alone for stage IB and IC endometrial cancer. Int J Radiat Oncol Biol Phys 2000;46:417–25. [43] Solhjem MC, Petersen IA, Haddock MG. Vaginal brachytherapy alone is sufficient adjuvant treatment of surgical stage I endometrial cancer. Int J Radiat Oncol Biol Phys 2005; 62:1379–84. [44] Eltabbakh GH, Piver MS, Hempling RE, et al. Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma
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HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Radiation Therapy for Gynecologic Malignancies Kristin A. Bradley, MDa,*, Daniel G. Petereit, MDa,b a
Department of Human Oncology, University of Wisconsin Medical School, University Hospital & Clinics, K4/B100 Radiotherapy, 600 Highland Avenue, Madison, WI 53792, USA b John T. Vucurevich Cancer Care Institute, Radiation Oncology, Rapid City Regional Hospital, Rapid City, SD, USA
T
he American Cancer Society estimates that in 2005, 660,000 new female cancers will be diagnosed in the United States, and 275,000 women will die of their disease [1]. Of these new cancers, approximately 80,000 will be gynecologic in origin, resulting in an estimated 29,000 deaths [1]. Table 1 compares the 2005 estimates for new cases of gynecologic malignancies with mortality rates for each tumor type. Although tumors of the uterine corpus rank first among new cases of gynecologic malignancies (41,000 new cases in 2005), ovarian cancer has the highest mortality rate at 16,000 [1]. Radiation therapy has long played an important role in the therapeutic management of cancers, including gynecologic malignancies. At the end of the nineteenth century, following the discovery of X-rays by Roentgen in 1895 [2] and the discovery of radium by Marie and Pierre Curie in 1898 [3], the first patient was treated with therapeutic X-rays. During the first few decades of the twentieth century, the use of radiation increased significantly. Some of the earliest uses of therapeutic radiation involved treating gynecologic malignancies, especially uterine tumors. Shortly thereafter, multiple papers were published in Europe and the United States reporting the use of X-rays and radium to treat carcinoma of the uterine cervix [4–7]. In the infancy of therapeutic radiotherapy not much was known or understood about how radiation affects tumor and adjacent normal tissues. As a result, treatment failures and radiation-associated toxicities were frequent. Despite early difficulties, fractionated radiation schedules were quickly developed and became the basis for modern radiation therapy [8]. The importance of brachytherapy was soon recognized as high doses could be delivered while sparing the adjacent normal tissues because of the rapid dose fall off. It became apparent that locally advanced cervical cancer could be cured with brachytherapy, and after 1910, several other anatomic sites were also treated with this modality [9].
* Corresponding author. E-mail address: [email protected] (K.A. Bradley). 0889-8588/06/$ – see front matter doi:10.1016/j.hoc.2006.01.019
© 2006 Elsevier Inc. All rights reserved. hemonc.theclinics.com
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Table 1 2005 Estimates for new gynecologic cancer cases and deaths Cancer origin
Number of new cases
Number of deaths
Uterine corpus Ovarian Cervix Vulva Vagina and others All gynecologic sites
40,880 22,220 10,370 3870 2140 79,480
7310 16,210 3710 870 810 28,910
Data from American Cancer Society. Estimated new cancer cases and deaths by sex for all sites, US, 2005. Available at: http://www.cancer.org. Accessed October 10, 2005.
Over the past 100 years radiation therapy has become an integral treatment modality in the management of various malignancies. For some disease sites its use has decreased in popularity and for others its use has grown dramatically. Currently it is an important therapeutic component in the management of many gynecologic malignancies, including cancer of the uterine cervix, uterine corpus, vulva, and vagina. Although often combined with surgery and chemotherapy, radiation therapy also has a definitive therapeutic role for many cervical, vaginal, and vulvar carcinomas. In this article, the current role of radiation therapy in the treatment of gynecologic malignancies as definitive and adjuvant therapy is reviewed. In addition, the most common radiotherapy techniques used to treat gynecologic cancers and the radiation-related toxicities are discussed. RADIATION THERAPY BASICS Therapeutic radiation can be categorized by the method of production. For example, high-energy machines such as linear accelerators generate external beam radiation through the production of electron beams or X-rays, whereas brachytherapy sources generate gamma ray irradiation through the decay of unstable radioisotopes such as iridium and cesium. Most commonly, radiation therapy involves external beam treatments using X-rays or electrons. The X-rays (photons) and electrons used in radiation oncology are of much higher energy than those used in diagnostic radiology. Most linear accelerators are capable of generating therapeutic X-rays and electrons of various energies. This results in beams with different tissue-penetrating characteristics, making the treatment of malignancies in various anatomic locations possible. In general, higher energy beams are used to treat gynecologic cancers, in which the deeper abdominal and pelvic tissues are the targets. Traditionally, external beam radiotherapy is delivered in multiple daily fractions over several weeks. Dividing the total dose of radiation into multiple smaller fractions spares normal tissue through repair of sublethal damage and repopulation between fractions. In addition, fractionation increases tumor cell kill because reoxygenation and reassortment of cells into sensitive phases of the cell cycle occurs between fractions.
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Although treatment breaks may decrease the acute toxicities of radiation, they may also compromise cervical cancer cure rates owing to the accelerated repopulation of tumor clonogens. With treatment prolongation, surviving tumor cells proliferate more rapidly and become increasingly radioresistant. This phenomenon was shown in a study by Petereit and colleagues [10] in which each additional day of treatment beyond 55 days decreased survival by 1%. The dose-rate is crucial in determining the consequences of a given dose of radiation. Classically, the biologic effect of radiation is reduced as the dose-rate is decreased and the exposure time extended because of the repair of sublethal damage that occurs during prolonged radiation exposure. External beam radiation therapy and high–dose-rate brachytherapy deliver radiation at a dose-rate that does not allow for repair of sublethal damage during the delivery of a given fraction of radiation. To compensate for the loss of sublethal damage repair during treatment, the dose per fraction is lowered to allow for normal tissue repair. INNOVATIONS IN EXTERNAL BEAM RADIATION THERAPY Three-Dimensional Conformal Radiation Therapy Just a few years ago most patients receiving radiation therapy were treated using conventional planning. In this process, a patient undergoes a simulation in which fluoroscopic radiographs are obtained. The physician then outlines the treatment fields to target the tumor while blocking out the normal tissues. Although this technique is still used, most commonly to palliate bone and brain metastases, the majority of radiation oncology facilities use three-dimensional (3-D) conformal radiation therapy (CRT) for planning and treatment delivery. The goal of 3-D CRT is to conform the delivered radiation to the tumor while decreasing the dose to the surrounding normal tissues. To accomplish this, a patient undergoes a planning CT scan with the patient in the treatment position. The CT images are then transferred to a computer equipped with 3-D visualization and planning software. The physician contours the tumor and critical normal structures on every slice. A treatment plan is generated and evaluated by the physician to assess the optimal dose distribution. Intensity-Modulated Radiation Therapy Intensity-modulated radiation therapy (IMRT) is a more specialized 3-D CRT technique used to further minimize the normal tissue dose. Like the 3-D CRT process described above, a planning CT scan is performed and the treatment plan is generated on a computer. IMRT differs from the standard 3-D CRT approach in that the physician defines the target dose and then establishes dose constraints or limits for normal structures. Once this is done, an optimal treatment plan is generated by way of computer algorithms that modulate the intensity of the radiation beams. This process creates a large number of sub-beams with varying radiation intensity, resulting in steep dose gradients between the tumor and adjacent structures. IMRT has the potential to widen the therapeutic window either by dose escalation with higher biochemical control rates as in
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prostate cancer or by conformal avoidance to reduce complications such as xerostomia for head and neck cancers. IMRT increasingly is being investigated for gynecologic cancers either to reduce the small bowel or bone marrow dose or to dose escalate the pelvic or para-aortic lymph nodes [11–14]. Mundt and colleagues [14] reported a significant reduction in dose to the bone marrow with IMRT compared with standard pelvic radiotherapy. Patient and organ motion remain major constraints that prevent wider implementation of this technology, as documented in a recent study by Ahamad and coworkers at the M.D. Anderson Cancer Center [11]. Until these issues of pelvic organ motion and reproducibility of patient positioning are resolved, IMRT for gynecologic malignancies may not become as commonplace as IMRT for cancers of other anatomic sites. BRACHYTHERAPY Brachytherapy, or radiation delivered at a close distance, is a widely used technique that has been in existence for more than a century. It is used either alone or in conjunction with external beam radiotherapy to treat various cancers. It consists of placing radioactive sources close to or in contact with the tumor. Treatments vary depending on the dose-rate, mode of surgical implantation, and whether the brachytherapy implant is permanent or temporary. In the past, most brachytherapy treatments were low–dose-rate (LDR), but high– dose-rate (HDR) brachytherapy use has increased dramatically in the past several years because treatments are delivered in a few minutes, thereby permitting outpatient therapy. In addition, the computer-controlled remote afterloading device eliminates radiation exposure to the physician and the nursing staff. LDR techniques were developed in an era when remote afterloading technology was unavailable, and remote afterloading techniques were developed because of concerns about radiation exposure to health care workers. For many years, available technology only allowed brachytherapy treatments for short duration, and it was therefore necessary to deliver remote afterloading brachytherapy at high dose-rates [15]. In more recent years, new technology has allowed remote afterloading brachytherapy to be given at low dose-rates as well. Even though biologic advantages for LDR are claimed, there are additional advantages for HDR brachytherapy, including rigid immobilization, outpatient treatment, patient convenience, and potential cost savings [16–18]. Brachytherapy, although now used in radiation therapy to treat many different tumor types, has long played a role in the treatment of gynecologic malignancies. It remains an essential component in the definitive treatment of cervical carcinoma with radiation therapy. CERVICAL CANCER Although the incidence of cervical carcinoma in the United States has declined over the last few decades because of the widespread use of Papanicolaou screening, cervical cancer remains one of the leading cancer killers of women worldwide. Treatment of cervical carcinoma depends on the stage at diagnosis. The International Federation of Gynecology and Obstetrics (FIGO) clinical staging
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system is used. It allows for basic evaluations and studies to stage the patient’s disease, but does not incorporate information gained from modern imaging such as CT, MRI, or positron emission tomography (PET). By excluding the findings from these radiographic studies one can compare outcomes for patients treated across the world, including nations where cervical cancer is common but the availability and use of these imaging modalities is not. Positive findings from CT, MRI, or PET scans do not change the patient’s stage, but do influence the prognosis and may alter treatment decisions. CT is useful for identifying hydronephrosis and enlarged pelvic and para-aortic lymph nodes; MRI is used to identify parametrial extension and rectal or bladder invasion; and PET has been shown to be more sensitive than CT for detection of nodal disease and distant metastasis [19,20]. A study by Grigsby and colleagues [20] highlighted the impact of PET and the poor prognosis conferred by lymph node positivity. In this study, 2-year progression-free survival according to CT and PET findings for pelvic lymph nodes was 73% if CT and PET negative, 49% if CT negative but PET positive, and 39% if CT and PET positive, P = .001. Patients who had para-aortic lymphadenopathy had a worse outcome with 2-year progression-free survivals of 64% if CT and PET negative, 18% if CT negative but PET positive, and 14% if CT and PET positive, P < .001. Because of the impact lymph node metastasis has on survival, the use of PET is increasing to assist with treatment planning and to counsel patients about their overall prognosis [21]. In January 2005, the Centers for Medicare and Medicaid Services approved the use of 18F-2-deoxy-2-fluoro-D-glucose PET (18F-FDG-PET) imaging for the initial staging of cervical carcinoma [22]. Treatment for cervical cancer depends primarily on the stage of disease. Table 2 summarizes treatment options and outcomes by stage. For early microinvasive cervical carcinoma (FIGO IA1), options include a simple hysterectomy or radiotherapy. In larger microinvasive tumors (IA2 or IB1 disease), a radical hysterectomy with a pelvic lymphadenectomy or definitive radiotherapy achieves equivalent local control and survival [23,24]. Radical surgery may be used to treat patients who have stage IB2 and IIA disease, but because of
Table 2 Treatment options and outcome for cervical carcinoma by International Federation of Gynecology and Obstetrics stage FIGO stage
Treatment options
5-y overall survival (%)
IA1 IA1, IA2 IB1 IB2, IIA IIB III IVA IVB
Simple hysterectomy, radiation therapy Radical hysterectomy, radiation therapy Radical hysterectomy, radiation therapy Chemoradiation therapy, radical hysterectomy Chemoradiation therapy Chemoradiation therapy Chemoradiation therapy, exenteration Palliation
>95 >95 80–90 80 65–75 30–50 10–20 <5
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the frequent need for postoperative radiation therapy based on surgical pathologic findings, many institutions recommend definitive radiation therapy in an attempt to avoid the combined toxicities of surgery and radiation. For more advanced stages (FIGO IB2 to IVA), definitive radiation therapy has been used successfully to treat cervical cancer for nearly a century. Standard therapy consists of carefully planned, high energy external beam radiotherapy combined with brachytherapy, either LDR or HDR. Using radiation alone, cure rates as high as 50% to 90% for patients who have stage IB to IIIB disease can be achieved [25–27]. Traditionally, definitive radiotherapy alone has been the standard of care for treating cervical carcinoma. In 1999, the National Cancer Institute (NCI) issued an alert that chemotherapy should be added to primary radiation therapy for cervical cancer. This alert was based on data from five cooperative grouprandomized trials that showed an overall survival advantage for cisplatinbased chemoradiation therapy compared with radiation therapy alone [28–32]. The studies included either FIGO stage IB2 to IVA patients treated with primary radiation therapy or stage I to IIA patients treated with primary surgery and found to have positive lymph nodes, parametrial extension, or positive surgical margins. The chemotherapy regimens that were used varied, but were all cisplatin based. The relative survival improvements demonstrated by these trials were 30% to 50%, with an average absolute survival benefit of 10%. The NCI Canadian study did not show a benefit with the addition of chemotherapy to radiation [33]. The investigators postulated that a survival benefit was not observed with the addition of chemotherapy because optimal radiation parameters were achieved, such as avoidance of treatment prolongation (radiation was completed in 7 weeks) and minimization of anemia (hemoglobin levels were maintained at 11 g/dL). Because most of the published randomized data support the use of concurrent chemotherapy, it is considered standard therapy for patients who have stages IB2 or higher or in the postoperative setting with positive nodes, parametria, or surgical margins. Off study, the most common chemotherapy regimen consists of cisplatin alone at 40 mg/m2/wk for 5 to 6 weeks concurrent with radiation. Definitive radiotherapy for cervical cancer includes both external and internal radiation modalities. External beam radiation therapy is directed daily to the pelvis and sometimes to an extended field that includes the retroperitoneal lymph nodes over 5 to 6 weeks. Typical doses to the whole pelvis are 45 to 50.4 Gy at 1.8 to 2 Gy/fraction with fields designed to encompass the primary cervical disease, any parametrial or vaginal extension, and the lymph node chains at risk, including the hypogastrics and external iliacs. Known parametrial disease or positive nodes are then “boosted” to a higher dose, ranging from 50.4 to 60 Gy. Most commonly, the radiation fields are designed using 3-D, CT-based planning that allows for visualization of the cervix, bladder, vessels, lymph nodes, and other anatomic structures. As mentioned earlier, MRI and PET findings do not change the stage of the tumor, but can be used to assist with radiation treatment planning. Generally, there are either two or
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Fig. 1. Tandem and ovoids applicator used for high–dose-rate brachytherapy for cervical cancer.
four radiation fields, coming in from anterior, posterior, right lateral, and left lateral directions. IMRT is currently under investigation to determine if toxicities can be decreased by reducing doses to the adjacent normal tissues and if higher doses can be safely administered to lymph nodes containing metastatic disease [11–14]. Brachytherapy, or internal radiation, is a crucial part of potentially curing advanced cervical carcinoma because high doses can be delivered to the tumor while sparing the bladder and rectum because of the rapid dose fall off. The choice of brachytherapy, either LDR or HDR, is usually institution driven with HDR increasing in popularity for reasons previously discussed. Different radioisotopes are used in brachytherapy and are chosen based on their unique combination of properties including energy, half-life, physical size, and safety issues. For gynecologic malignancies, either Iridium-192 or Cesium-137 is used for LDR, and Iridium-192 is used for HDR in the United States. Brachytherapy is delivered using various techniques and applicators. Brachytherapy for cervical carcinoma uses an intrauterine applicator, called a tandem, and either vaginal ovoids (Figs. 1 and 2), vaginal cylinders, or a vaginal ring. LDR usually requires one to two insertions, whereas HDR requires three to five.
Fig. 2. Lateral fluoroscopic image of tandem and ovoids in a patient with cervical cancer.
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With either method of dose-rate delivery, brachytherapy is initiated at some point during external beam radiation once optimal tumor reduction is achieved, that is, tumor size less than 4 cm. Depending on the tumor size, 2 to 5 weeks of external beam radiation may be necessary before adequate cervical regression occurs. Because LDR brachytherapy requires one to two insertions, this can be delivered near the end of or after completion of external beam radiation, whereas HDR insertions begin sooner to minimize the overall treatment duration. It is common to perform two HDR fractions per week as external beam treatments continue on the other days of the week. Patients do not receive both external beam and brachytherapy on the same day. Intravenous conscious sedation is administered during each procedure for patient comfort. On occasion, a spinal or general anesthetic is necessary. The total dose prescribed to the paracervical tissues (Point A) is in the range of 80 to 85 Gy when using LDR. With HDR, the total dose is lower because of the dose-rate effect. Comparable biologically effective doses are prescribed in both systems, however. It is critical that the total doses to the bladder, rectum, and sigmoid remain below a certain level to minimize complication rates. Three randomized trials and several single institutional experiences have documented the equivalency of HDR to LDR [34–36]. ENDOMETRIAL CANCER Endometrial cancer is the most common gynecologic malignancy, with an estimated 41,000 cases in 2005. Standard treatment consists of an extrafascial hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and an assessment of the pelvic and para-aortic lymph nodes. Fortunately, because of the presence of early symptoms such as vaginal bleeding, most patients are diagnosed at an early stage. The need for adjuvant postsurgical therapy depends on surgical and pathologic findings. For stage I patients who have uterine-confined disease, the indications for adjuvant radiation therapy continue to evolve and are based on the patterns and risk for recurrence in addition to the efficacy of additional treatment. The assessment of risk depends on the depth of myometrial invasion, tumor grade, lymphovascular space invasion (LVI), and degree of surgical staging of the lymph nodes. When a staging lymphadenectomy has not been performed or is incomplete, the findings of Gynecologic Oncology Group (GOG) #33 are helpful in estimating the risk for pelvic nodal involvement and recurrence [37,38]. Adjuvant radiation options include pelvic radiotherapy, vaginal cuff brachytherapy, or a combination of both. Pelvic radiation therapy is recommended for patients whose lymph nodes have not been surgically evaluated and who have a significant risk for microscopic spread to the nodes based on the depth of invasion and tumor grade. In general, these are patients who have deeply invasive tumors (stage IC) with intermediate- to high-grade disease (grade 2–3). Two randomized trials investigating the efficacy of pelvic radiotherapy have been published [39,40]. GOG #99 randomized patients after complete surgical staging to either observation or pelvic radiotherapy [40]. Most patients had well or moderately differentiated tumors (80% grade 1–2) that invaded one half or
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less into the myometrial wall (60% stage IB). Pelvic radiation therapy decreased recurrences at 2 years (12% observation versus 3% pelvic radiation, P = .007), but did not impact survival at 4 years (86% observation versus 92% radiation, P = .557). Additional analysis demonstrated an unfavorable group with highrisk features (approximately one third of the patients) who accounted for two thirds of the recurrences. High-risk features included outer third myometrial invasion, grade 2–3 disease, and the presence of lymphovascular space invasion. For women 50 years of age or older with two high-risk features, or women 70 years of age or older with one high-risk feature, the 2-year cumulative incidence of recurrence was 26% without pelvic radiation and 6% with radiation. In these well staged patients who had surgical lymph node staging, the most common site of preventable failure was the vaginal apex. The isolated vaginal cuff recurrence rate was 0.5% for those irradiated and 7.8% for those who were not. There was no statistically significant difference in the small bowel obstruction rate between the treatment arms; however, six of the seven patients who developed a grade 3 or 4 obstruction received pelvic radiotherapy. A European randomized trial also compared pelvic radiotherapy to observation after surgery for a similar patient cohort [39]. Unlike GOG #99, however, this study did not permit staging lymphadenectomies. Local–regional recurrences were reduced from 14% to 4% with the addition of pelvic radiotherapy (P < .001), with nearly 75% of the recurrences at the vaginal cuff. Survival was not significantly different between the observation and pelvic radiation groups as the 5-year actuarial survival was 81% in the radiotherapy group and 85% in the control group (P = .31). Patients who received adjuvant radiotherapy experienced a 2% significant complication rate, primarily enteric, versus 0.3% in the observation group. Vaginal cuff brachytherapy is a cost-effective, low-morbidity alternative to external beam radiotherapy that treats the site of greatest risk for recurrence in many patients. Because the vagina is the most common site of failure and external beam radiotherapy is associated with a significant small bowel obstruction rate of up to 10% for completely staged patients, vaginal cuff brachytherapy alone is often recommended for both low- and intermediate-risk stage I endometrial patients. Brachytherapy alone also has been used for highrisk stage I patients after a lymphadenectomy; however, failure patterns tend to be more distant than with pelvic radiotherapy [41–43]. Vaginal cuff brachytherapy has significantly less toxicity and affords nearly the same protection against recurrences as pelvic radiotherapy [44–46]. Vaginal cuff brachytherapy generally is delivered in three or four outpatient visits using HDR Iridium-192, whereas pelvic radiation therapy requires 5 to 6 weeks of daily treatment. The decision to recommend pelvic radiation versus vaginal cuff brachytherapy continues to evolve and varies among gynecologic and radiation oncologists. The investigators’ recommendations for pelvic radiation or vaginal cuff brachytherapy for stage I patients are detailed in Table 3. With short follow-up, GOG #99 and the European postoperative study (PORTEC) reported high salvage rates of approximately 80% for isolated vagi-
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Table 3 Suggested guidelines for adjuvant radiation therapy for stage I endometrial cancer with adequate lymphadenectomy FIGO stage
Grade 1
Grade 2
Grade 3
IA (no myometrial invasion) IB ( ≤ 50% myometrial invasion) IC ( ≥ 50% myometrial invasion)
None
None
Vaginal cuff brachytherapy
None
Vaginal cuff brachytherapy Pelvic radiation
Vaginal cuff brachytherapy or pelvic radiationa Pelvic radiation
a
Vaginal cuff brachytherapy or pelvic radiationa
If lymphovascular space invasion or suboptimal lymphadenectomy, favor pelvic radiation therapy.
nal cuff recurrences [39,40]. Data from the M.D. Anderson Cancer Center suggest that these initially high salvage rates are not durable with longer follow-up [47]. Although the 2-year pelvic control and survival rates were encouraging (82% and 75%), these rates dropped to 69% and 43%, respectively, at 5 years. This further reduction in survival at 5 years was because of the development of metastatic disease. This drop in survival at 5 years is critical because the data at 2 years is comparable to the results at 2 years in both the PORTEC and GOG trials. With longer follow-up, it is anticipated that these high salvage rates will not be durable. Therefore the necessity of preventing vaginal recurrences with adjuvant radiotherapy is crucial. For stage II endometrial cancer with involvement of the cervix, the choice of pelvic irradiation or vaginal cuff brachytherapy alone depends on the depth of myometrial invasion, tumor grade, adequacy of lymphadenectomy, and the extent of cervical invasion. With cervical stromal invasion (stage IIB), a combination of pelvic radiation and vaginal cuff brachytherapy is usually recommended. Until recently, adjuvant radiation was commonly used for stage III–IV nonmetastatic endometrial cancer. With the results of GOG #122, there has been an increase in the use of chemotherapy and a decrease in the use of radiation therapy [48]. This phase III study randomized nonmetastatic stage III–IV patients to whole abdominal radiotherapy (WAR) with a pelvic boost, or platinum-doxorubicin chemotherapy. The patients in the chemotherapy arm had superior progression-free survival (59% versus 46% at 2 years, P < .01) and overall survival (70% versus 59% at 2 years, P < .01) compared with the patients in the radiation arm. Unfortunately, approximately 55% of the patients who had advanced endometrial cancer still had recurrence. Many of the patients who underwent WAR in GOG #122 were not ideal radiation candidates in that they had bulky disease above the pelvis. WAR is typically only recommended if there is microscopic disease above the pelvis. Current efforts integrating both effective systemic therapies and radiation therapy to high-risk areas, that is, pelvic radiotherapy or brachytherapy, will most likely be needed to optimize cure rates.
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VULVAR CANCER The incidence of vulvar and vaginal cancer in the United States is considerably lower than that of other gynecologic malignancies. The role of radiation therapy in the management of these two diseases, however, is considerable. For early stage vulvar cancer (T1–T2), surgery with a radical wide local excision and inguinal lymph node dissection is the preferred treatment. The indications for postoperative radiation therapy are positive surgical margins, margin less than 8 mm, two or more inguinal lymph nodes positive, a grossly positive lymph node, or extracapsular nodal extension. Adjuvant radiation is sometimes considered for tumors that do not meet the above criteria but are deeply invasive and have lymphovascular space invasion. The rationale for treating patients who have close or positive margins comes from a study by Heaps and colleagues [49] in which the local recurrence rate was 48% if the margin was less than 8 mm compared with 0% if the margin was 8 mm or greater, P < .001. Of the patients who had margins less than 8 mm, half were observed after surgery and the other half received adjuvant radiation therapy to the vulva. The patients receiving radiation had lower local recurrence rates and improved survival compared with the patients who did not receive radiation. The GOG reported results of a randomized trial in which patients who underwent a radical vulvectomy and bilateral groin node dissection were randomized to a pelvic lymph node dissection or pelvic and inguinal radiation therapy if the inguinal lymph nodes were pathologically positive intraoperatively [50]. The study closed early when an interim analysis showed a statistically significant survival advantage for the radiation arm: 2-year survival rate of 68% for the radiation group compared with 54% for the pelvic node dissection group (P = .03). The advantage was most dramatic for patients who had a grossly positive node or two or more positive inguinal lymph nodes. There was no significant difference in survival for patients who had one microscopically positive node. In the postsurgical setting, radiation can be directed to the pelvis and groins, the vulva alone, or the primary site and draining locoregional lymphatics, depending on the risk factors for local recurrence and metastatic lymph node spread. Typical adjuvant doses are 45 to 50 Gy delivered over 5 to 5.5 weeks of daily treatment. Various radiation techniques are used to ensure adequate coverage of the target tissues. For more advanced vulvar cancer that involves or is adjacent to the anus, clitoris, or urethra, the recent trend has been toward neoadjuvant or primary chemoradiation to avoid exenteration and permit a less radical and debilitating surgery. There have been numerous small studies investigating this approach, but no randomized trials have been published. Based on the success of these smaller, single-institution studies, the GOG is currently conducting a phase II study of chemoradiation for locally advanced vulvar carcinoma [51–54]. In the open GOG study, radiation is delivered to the primary tumor, pelvis, and inguinal regions to 45 Gy followed by a boost to the primary tumor to 57.6 Gy, all delivered with concurrent weekly cisplatin. After 6 to 8 weeks, response to
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chemoradiation is assessed. Patients who have a partial response undergo resection of the residual disease. VAGINAL CANCER Radiation therapy is usually the treatment of choice for all stages of vaginal cancer to avoid exenterative surgery and potentially preserve sexual function. The exception is stage I disease involving the upper one third of the vagina where a radical hysterectomy may be considered. Selected patients who have limited, superficial disease can be treated with intracavitary vaginal brachytherapy alone, but most patients receive a combination of external beam radiation therapy and brachytherapy. Interstitial brachytherapy using intraoperative needle placement is recommended for thicker, more extensive tumors to deliver adequate dose to the vagina and paravaginal tissues. Based on the benefit of adding chemotherapy to radiation therapy for cervical cancer, concurrent cisplatin-based chemoradiation therapy has been used to treat vaginal cancer as well. This extrapolation from cervical cancer to vaginal cancer is reasonable, as a randomized trial of radiation versus chemoradiation is unlikely to be undertaken for vaginal cancer because of its infrequency. OVARIAN CANCER Radiation therapy plays a limited role in the management of ovarian carcinoma. Patients undergo a staging laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, tumor debulking, and assessment of the pelvic and para-aortic lymph nodes. After optimal surgical cytoreduction, adjuvant chemotherapy is recommended for most patients. In the past, whole abdominal radiation or intraperitoneal radiocolloid ( 32P ) instillation were used to treat the entire peritoneal cavity that is at risk. Because of the increased risk for late bowel complications associated with postoperative radiation, chemotherapy has eclipsed radiation therapy as the standard adjuvant therapy [55]. External beam radiation still has an important and effective role in the palliation of symptomatic recurrences. Approximately 50% to 75% of patients experience significant symptomatic relief from a short course of external beam radiation [56]. SUMMARY In the last century, radiation has been successfully used as primary and adjuvant treatment in the management of gynecologic malignancies. It is anticipated that radiation will continue as an integral component in the treatment of cervical, endometrial, vulvar, and vaginal carcinoma. Current efforts are directed at improving control rates while minimizing treatment-related toxicities through the use of more conformal external beam radiotherapy techniques, refinement of brachytherapy techniques, and the integration of chemotherapy. References [1] American Cancer Society. Estimated new cancer cases and deaths by sex for all sites, US, 2005. Available at: http://www.cancer.org. Accessed October 10, 2005. [2] Roentgen WC. On a new kind of rays (preliminary communication). Translation of a paper
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