Radiation Therapy in Gynecology

INTRODUCTION

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Gynecologic cancers were among the first malignancies treated with ionizing radiation more than a century ago. Today, radiation therapy remains an essential component of both the primary non-surgical management and adjuvant postoperative treatment of selected malignancies arising in the female reproductive tract.

Current strategies for treating cancers of the uterine corpus, uterine cervix, vulva, and vagina are tailored to the clinical and pathological stage of disease. Early stage lesions of the lower genitourinary tract can be treated surgically if resection can be accomplished without significant tissue disruption. Postoperative radiotherapy is reserved for cases in which histopathologic analysis of the removed specimen reveals features suggesting a high risk for local recurrence.

Primary radiotherapy can provide a chance for cure for women with unresectable, locally advanced disease or for those women with medical risk factors that contraindicate primary surgical therapy. Unfortunately, for women with distant metastatic disease at presentation, disease cure is unlikely. Palliative radiotherapy can frequently improve a patient's quality of life when used for the relief of symptoms. Although adjuvant radiotherapy is commonly used for advanced or metastatic cervical and endometrial cancer, it is infrequently employed as adjuvant therapy for ovarian cancer. Radiation therapy may be also be used for hormonal ablation.

CARCINOMA OF THE UTERINE CORPUS

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Endometrial carcinoma is the most common gynecologic cancer in the US. Approximately 40,000 women are diagnosed with endometrial adenocarcinoma annually in the US. Acknowledged risk factors include diabetes, hypertension, and obesity. The typical patient is postmenopausal and presents with painless vaginal bleeding without visible or palpable abnormality on pelvic examination. Premenopausal patients frequently present with irregular menstrual periods, often associated with heavy bleeding.

The diagnosis is established by endometrial biopsy, and the most common histologic subtype is endometrioid adenocarcinoma arising from the glandular epithelium lining the uterine cavity. Less common histologic variants include uterine papillary serous carcinoma (UPSC), clear cell carcinoma, and carcinosarcoma, also known as malignant mixed Müllerian tumor (MMMT). Lymphomas rarely occur in this site. The uterus can be a site of secondary involvement from ovarian or cervical carcinoma or a site of metastatic spread from primary breast or other carcinoma.

Preoperative studies include a chest radiograph, complete blood count, and serum chemistries for women without evidence of extra-uterine disease. Surgical resection is the preferred initial treatment when medically feasible. When hysterectomy is medically contraindicated, primary radiotherapy can offer 5-year disease-specific survival rates of 80-90%, approaching those achieved with surgery.

The American Joint Committee on Cancer staging guidelines, summarized in the table below, are based on surgical findings. Recommendations for adjuvant postoperative therapy are influenced by the depth of invasion and histopathologic grade of the tumor. Grades 1, 2, and 3 correspond to well differentiated, moderately differentiated, and poorly differentiated tumors, respectively.

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An abdominal hysterectomy (including removal of the uterine corpus and cervix, fallopian tubes, and ovaries) is the traditional primary surgical therapy. Pelvic washings for cytopathologic analysis are obtained prior to surgical dissection. Total abdominal hysterectomy and bilateral salpingo-oophorectomy usually suffice for therapy of well-differentiated tumors, unless intra-operative examination reveals evidence of deep myometrial invasion or spread to the uterine cervix. For moderately or poorly differentiated tumors or well differentiated tumors with deep myometrial invasion or spread to the cervix, pelvic and para-aortic lymph nodes should be sampled at the time of hysterectomy.

Whole pelvic external beam radiotherapy (XRT) and intra-vaginal brachytherapy (IVB) are commonly used as adjuvant postoperative therapy for patients with stage I disease. Recommendations are based on the sub-stage and grade of disease. The guidelines employed currently at the Medical College of Virginia are outlined in the table below.

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The use of IVB in cases of stage IB grade 1 or IB grade 2 was supported by the randomized studies conducted in the 1960s and 1970s at the Roswell Park Institute. In those studies, IVB significantly reduced the incidence of vaginal recurrence to less than 1%. In contrast, a recent large randomized study conducted in the Netherlands confirmed that minimal benefit would be gained by adding whole pelvic radiotherapy for patients with tumors of such generally favorable prognosis.

For patients with deeply invasive high-grade tumors, the use of pelvic XRT in addition to IVB was demonstrated by a randomized study at the Norwegian Radium Hospital to improve recurrence-free survival. More recently the Gynecologic Oncology Group (GOG) has undertaken a similar study to evaluate the role of pelvic XRT alone as adjuvant therapy over a broad range of patients with stage I endometrial cancer. Preliminary analysis has suggested a beneficial effect from the pelvic XRT.

Whole pelvic XRT may be administered through a 4-field setup involving parallel opposed anteroposterior (AP), posteroanterior (PA), right lateral, and left lateral fields. Patients are positioned prone upon a partially depressed surface that allows anterior displacement of the small intestines away from the lateral fields. A radiopaque marker in the vagina at the time of simulation facilitates identification of the vaginal cuff. Typical field borders are the following:

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• Superior (all fields) L4-L5 or L5-S1 interspace
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• Inferior (all fields) middle or inferior aspect of the obturator foramen or at least 5 cm below the vaginal cuff
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• Lateral (AP and PA fields) 1.5-2.0 cm lateral to bony pelvis
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• Anterior (lateral fields) anterior pubic symphysis, blocking out portions of small bowel anterosuperior to the external iliac nodal chain
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• Posterior (lateral fields) posterior aspect of S3, covering the region of insertion of the uterosacral ligament, with at least a 2 cm margin posterior to the vagina inferiorly

CARCINOMA OF THE UTERINE CERVIX 1: MANAGEMENT PRINCIPLES

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Among women in the US, the annual incidence of invasive carcinoma of the uterine cervix is approximately 13,000. The most common risk factor is exposure to the human papilloma virus. The Pap smear is an effective screening tool for identification of premalignant changes. In countries when high-risk features are revealed by Pap smear and where hysterectomy, conization, and cervical epithelial ablation are routinely performed, the incidence of cervical cancer has diminished.

Patients with cervical cancer typically present with irregular vaginal bleeding. Physical examination usually reveals a mass distorting the cervix. A biopsy is necessary to confirm the diagnosis. The most common histologic subtype is squamous cell carcinoma. Adenocarcinoma of the cervix is next common followed by uncommon histologic variants, small cell carcinoma and adenoid cystic carcinoma.

For occult lesions detected by an abnormal Pap smear or small (less than approximately 3 cm) well-circumscribed ectocervical lesions without clinical suspicion of parametrial extension, biopsy should be performed to confirm the presence of invasive disease. Otherwise healthy women may then proceed directly to hysterectomy. In other cases, initial staging workup should include a chest radiograph and intravenous urography (or other imaging) to determine the presence or absence of hydronephrosis.

Cystoscopy and proctoscopy are standard complementary procedures at many institutions. Although not incorporated in the clinical staging system, abdominopelvic computerized tomography (CT) scan or lymphangiogram can provide helpful information about the status of pelvic and para-aortic lymph nodes. Anemia is known to be an indicator of poor prognosis, especially for patients receiving radiotherapy as the primary form of treatment.

The American Joint Committee on Cancer staging guidelines for cervical cancer are summarized in the table below. Stage IA is further subdivided according to whether there is more or less than 3-mm depth of stromal invasion. Lesions deeper than 5 mm or horizontally spread more than 7 mm are categorized as IB, as are all clinically visible lesions confined to the cervix. The para-aortic lymph nodes are considered a distant metastatic site.

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?/P>For stages IA-IB1, hysterectomy is potentially curative. For stage IB1, the procedure of choice is a radical hysterectomy with resection of the parametria and pelvic lymph node dissection. Para-aortic lymph nodes should be examined and sampled if suspicious for metastatic disease. If parametrial extension or regional nodal metastasis is identified intraoperatively, many gynecologic oncologists will abort the hysterectomy and proceed to adjuvant pelvic radiotherapy.

Histopathologic features suggesting a high risk of pelvic recurrence include tumor size greater than 4 cm, capillary lymphatic space involvement, and invasion to a depth greater than one-third of the cervical stroma. For patients found to have at least 2 of these risk factors, postoperative pelvic radiotherapy has reduced the risk of disease recurrence. For patients found to have histopathologic evidence of tumor spread to regional lymph nodes, tumor present at the surgical margin, and/or microscopic involvement of the parametrium, postoperative radiotherapy combined with concurrent chemotherapy has been shown to improve survival when compared with postoperative radiotherapy alone. Postoperative pelvic XRT is recommended for cancers of stage IB1 or higher found incidentally after simple hysterectomy for presumed benign disease.

For stage IB and IIA lesions, 5-year survival of approximately 80% can be achieved with either radical hysterectomy and selective postoperative pelvic radiotherapy or radiotherapy alone. However, for lesions larger than 4 cm in greatest dimension, there is a high risk of pelvic recurrence. Because the use of pelvic radiotherapy after radical hysterectomy is associated with a significantly higher rate of severe toxicity than definitive radiotherapy alone, it is the policy at the Medical College of Virginia to recommend radiotherapy as the preferred primary modality of treatment for patients with early stage lesions greater than 4 cm in maximum dimension.

For reasons of avoiding additive toxicity from both surgery and radiotherapy, it is generally agreed that primary radiotherapy is indicated for management of higher stages (IIB-IVA) of locally advanced cervix cancer. Tumor resection with anterior and/or posterior pelvic exenteration is technically possible in some cases, but this procedure entails urinary tract and/or bowel diversion and is usually reserved for cases of isolated central pelvic disease persistence or recurrence following definitive radiotherapy.

CARCINOMA OF THE UTERINE CERVIX 2: RADIOTHERAPY TECHNIQUES

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Comprehensive radiotherapy for stages IB-IVA cervical cancer involves both external beam treatment and brachytherapy. Initial external beam fields encompass a clinical target volume (CTV) that includes the primary tumor and adjacent areas at risk for direct occult invasion or regional lymph node metastases. The field borders are usually similar to those shown above for endometrial cancer, with particular attention to coverage of the posterior extent of disease. The superior border is typically placed at the L4-L5 interspace, and elective radiotherapy to the para-aortic lymph nodes is added for patients with common iliac nodal metastases. For patients with gross disease in the para-aortic nodal region, retroperitoneal lymphadenectomy prior to XRT can improve the chance of disease control.

While there are acceptable variations to the dose schedule of combined pelvic XRT and brachytherapy for cervical cancer, a typical regimen would include an initial external beam dose of 40-45 Gy to the pelvis in fractions of 1.8-2.0 Gy. Cisplatin is usually given weekly at a dose of 40 mg per square meter of body surface area, with a maximum weekly dose of 70 mg. Because anemia can be exacerbated by the combined modality treatment, blood transfusions are commonly administered to maintain hemoglobin at or above 10-12 g/dL. Other toxicities of the combined modality treatment include electrolyte irregularities such as hypokalemia, hypomagnesemia, and hypocalcemia. Patients receiving this treatment should be monitored closely and given electrolyte replenishments when indicated.

Brachytherapy involves the temporary placement of intra-uterine tandem and intravaginal ovoid that are afterloaded with radioactive material. Device placement is performed under general anesthesia or heavy sedation. Radiopaque vaginal gauze secures the devices in place and fixes their relative position to the bladder and rectum. Intraoperative radiographs or digital fluoroscopic images document appropriate device positioning. Contrast material in a Foley catheter and a rectal tube can be used to aid in identifying the International Commission of Radiological Units (ICRU) reference points of interest described in the table below.

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Doses are prescribed to ICRU points A and B. The reference point of origin for points A and B is the cervical os, identified by a radiopaque flange adjusted and fixed at the time of tandem placement. It is helpful to place a non-radioactive gold seed marker beneath the epithelium surface near the os to corroborate localization of the os radiographically.

OVARIAN CANCER AND OVARIAN HORMONAL ABLATION

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Ovarian cancer is the second most common gynecologic malignancy in the US, with an expected annual incidence in excess of 23,000 cases. Unfortunately, there are no reliable screening methods available, and most patients present with advanced stage disease. Despite aggressive initial surgical resection and adjuvant postoperative therapy, over 60% of patients succumb to the disease. Consequently, ovarian cancer is the cause of more cancer-related mortality than any other gynecologic cancer, and a death toll of 14,000 is projected for the year 2000.

The current regimen for adjuvant therapy following surgery is combination chemotherapy with cisplatin and paclitaxel. Whole abdominal radiotherapy (WAR) has been used, but its popularity has waned in view of the more favorable toxicity profiles of current chemotherapy regimens. Techniques for WAR have included AP/PA field treatment to the entire peritoneal cavity to doses of 25-30 Gy in fractions of 1-1.5 Gy. It is advisable to maintain the kidney doses below 20 Gy and the whole liver doses below 30 Gy. Boost treatment to the pelvis and para-aortic lymph nodes may be combined with the WAR to give total doses of 45-50 Gy to these regions.

Palliative radiotherapy is frequently offered to patients who have focally symptomatic recurrence of ovarian cancer. The field arrangements and dose schedule would be predicated on the site of recurrence and overall status of the patient. For painful or hemorrhagic pelvic masses refractory to chemotherapy, a hypofractionated schedule of 14.8 Gy in 4 fractions administered within 2 days may be administered via AP/PA fields and then repeated once or twice at 2-4 week intervals to provide a helpful reduction in symptoms for most patients. Three monthly 10 Gy fractions are also reasonable, especially for patients with poor performance status and limited life expectancy where convenience and expediency are of paramount importance.

Radiotherapy can also be applied in settings where ovarian hormonal ablation is indicated, most commonly in the treatment of estrogen receptor-positive breast cancer in pre-menopausal women. Though not as popular in this country, where tamoxifen is more commonly used, radiotherapy can be highly efficacious and cost-effective. The large meta-analysis supporting the value of adjuvant hormone therapy for breast cancer included many studies in which radiotherapy was used to achieve ovarian ablation.

A dose of 10-20 Gy in 5-10 fractions is usually sufficient to eliminate ovarian hormone production. To allow limitation of the size of the radiotherapy field, the location of the ovaries should ideally be verified by CT scan. Alternatively, a field covering the pelvic soft tissues from 1-2 cm below the symphysis to the bottom of the sacroiliac joint will include the ovaries in almost all cases.

VULVAR AND VAGINAL CANCER

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Primary malignancies arising in the vagina or vulva are far less common than uterine, cervical, and ovarian cancers. The annual incidences of vaginal cancer and vulvar cancer are approximately 2000 and 3500 cases, respectively, in the US. Exposure to the human papilloma virus is a key risk factor, as is cigarette smoking for vulvar cancer.

The typical patient with vulvar carcinoma presents with a pruritic and/or tender lesion in the vulva easily detectable on physical examination. The most common histologic subtype is squamous cell carcinoma, though adenocarcinoma may arise from glandular structures in the region. Careful evaluation of the groin nodes is important. A pelvic CT scan may reveal suspicious nodes not detected by physical examination.

The table below includes the current AJCC staging guidelines for vulvar cancer. Stage I is further subdivided into lesion with no greater than 1 mm stromal invasion (stage IA) and those with greater than 1 mm invasion (IB). Stage IA lesions can usually be cured with local excision. For stage IB and stage II lesions, wide radical excision should be accompanied by inguinal-femoral lymphadenectomy on the ipsilateral side in all cases and bilaterally when the lesion approaches midline or there are any clinically suspicious regional nodes. The role of sentinel lymph node identification is currently being investigated in the GOG 173 protocol.

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?/P>For clinical stage I-II lesions, postoperative radiotherapy is indicated when there is pathologic evidence of inguinal node metastasis or close (less than 8 mm) margins of resection around the primary site. A dose of 45-50 Gy in fractions of 1.8-2.0 Gy is given to regions at risk for residual microscopic disease. For limited ipsilateral nodal involvement with no pathologic nodal involvement identified by contralateral dissection, the external beam fields are often reduced to cover only the hemi-pelvis. In the current GOG 185 protocol, post-operative radiotherapy is being compared with the same radiotherapy plus concurrent chemotherapy for node-positive patients.

It is important to use a proper technique for effective radiotherapeutic treatment of the groin node regions. The region of concern is located anterior to the ischium, and it is desirable to avoid excessive radiation dose to the femoral neck. Available options include a wide AP photon field prescribed to the depth of the external iliac artery as it crosses the inguinal ligament, supplemented by a narrower PA field to ensure adequate coverage of the pelvic nodes. Alternatively, electrons may be used for some or all of the inguinal node region coverage, but the energy must be carefully selected to achieve a sufficiently deep distribution of radiation dose to the full nodal area.