Lilie L. Lin
Gynecologic Cancers – Highlights
Key Recent Guidelines
RTOG pelvic lymph node guidelines (IJROBP 2011) for cervical cancers have been updated. (PMID 18037584)
RTOG consensus guidelines (IJROBP 2012) for the contouring of pelvic normal tissue when treating gynecologic cancer include recommendations for the contouring of the anus/rectum, sigmoid, bowel bag, bladder, uterus/cervix, ovaries/fallopian tubes, and bilateral femurs. (PMID 22483697)
New IMRT Treatment Options
FIGURE 20-8. Axial views of contours of a patient treated with adjuvant IMRT after hysterectomy for endocervical adenocarcinoma. Small bowel (green), sigmoid (yellow-green), rectum (brown), bladder (yellow), CTV nodes (red), and CTV vagina (orange).
• The vulva consists of all external genital structures including the labia majora, mons pubis, labia minora, clitoris, perineal body, vulvar vestibule containing the urethral meatus, hymenal remnant, greater and lesser vestibular glands, and the associated erectile tissues and muscles. Figure 20-1 shows the anatomy of the vulva.
• The vulva is bound by the anterior abdominal wall superiorly, the labial crural folds laterally, and the anus posteriorly.
• The labia majora form the lateral boundaries of the vulva and are composed of adipose and fibrous tissue. They fuse anteriorly to form the mons pubis, a hair-bearing region of tissue overlying the pubic symphysis. Posteriorly, they terminate 3 to 4 cm anterior to the anus where they are joined at the posterior fourchette.
• The labia minora are immediately medial to the labia majora and contain mainly connective tissue with little adipose tissue. Anteriorly, the labia minora divide into two parts with one part passing over the clitoris to form the prepuce and the other joining beneath the clitoris to form the frenulum. The duct opening for the greater vestibular glands (Bartholin glands) is situated at the junction of the labia minor and the vaginal vestibule.
FIGURE 20-1. External female genitalia. (From Westheimer R, Lopater S. Human Sexuality. Baltimore, MD: Lippincott Williams & Wilkins, 2003.)
• In addition to the clitoris, other midline structures below the mons include the urethral meatus, the vaginal opening, and the perineal body.
• Lymphatic drainage of the vulva and distal third of the vagina is primarily via the inguinal lymph nodes. These lymph nodes are found in the tissues overlying the femoral triangle which is bounded by the inguinal ligament superiorly, the sartorius muscle laterally, and the adductor longus muscle medially (Fig. 20-2).
• The vagina is a hollow, pliable, muscular organ that extends from the cervix to the vulva. It averages 7 to 8 cm in length.
• Lymphatic flow within the vagina is complex with an extensive interconnected network. Lymphatics in the upper vagina drain primarily through the lymphatics of the cervix. The anterior upper vagina drains into the internal iliac and parametrial nodes, whereas the posterior vagina drains into the inferior gluteal, presacral, and anorectal nodes. The lymphatic drainage of the lower vagina follows the vulva with lymphatic flow into the inguinofemoral nodes and then to the pelvic lymph nodes. Lesions within the mid-vagina can drain through either route.1
• As a result of the complex network of lymphatics in the vagina, particularly the terminal branches of the vaginal artery and adjacent to the vaginal wall, the external iliac lymph nodes are at high risk even in patients with distal vaginal tumors and as such should be addressed during the treatment planning.
1.3. Endometrium and Cervix
• The uterus is a hollow, muscular, thick-walled organ that lies in the pelvic cavity between the bladder and rectum. The uterus is divided into the fundus, body, and isthmus. The wall consists of an inner glandular mucosa and an outer smooth muscle myometrium.
• The cervix is an extension of the lower uterine segment and generally varies in length, averaging 3 to 4 cm, but this is dependent on age of the patient and other cervical or uterine factors. The cervix is divided into two components, the upper or supravaginal cervix and the lower or vaginal cervix. The external os is located centrally within the vaginal portion and connects to the endocervical canal, the internal cervical os, and the endometrial canal (Fig. 20-3).
FIGURE 20-2. Lymphatic drainage of the female pelvis. (Reprinted from Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:244.)
FIGURE 20-3. Diagram of the uterus and vagina illustrating the parts of the uterus and the relationship of its cervix to the superior end of the vagina.
• Five paired ligaments support the uterus: broad, round, uterosacral, cardinal, and vesicouterine. The uterosacral and cardinal ligaments are uncommonly involved in uterine cancer, contrary to cervical cancer.
• Blood supply of the uterus is through the uterine artery, a branch of the hypogastric artery.
• Lymphatic flow from the uterus can occur through four main drainage channels: from the fundus, along the round ligaments, along the mesosalpinx and fallopian tubes, and in the folds of the broad ligament. The drainage patterns are reflected in the metastatic potential to the pelvic and para-aortic lymph nodes (Fig. 20-4).
• The lymphatic flow of the cervix is complex. The most dominant route is laterally from the cervix: lymphatics drain into the paracervical and parametrial lymph nodes to the internal, external, and common iliac chains. The other routes of drainage include the inferior and superior gluteal lymph nodes, and the superior rectal, presacral, and para-aortic lymph nodes.
2. NATURAL HISTORY
• Over 90% of vulvar malignancies are squamous cell carcinoma. There are two distinct types:
º Keratinizing type generally occurs in older women and is unrelated to HPV infection, but associated with vulvar dystrophies. Verroucous carcinoma, a variant of squamous cell carcinoma has a cauliflower-like appearance and rarely metastasizes to lymph nodes, though it can be locally destructive.
FIGURE 20-4. Lymphatic drainage of the structures of the female pelvis. (Reprinted from Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:244.)
º Classic, warty, or Bowenoid type is associated commonly with HPV 16, 18, and 33 and tends to occur more often in younger women.
• Vulvar cancers metastasize by a variety of methods:
º Direct extension to nearby organs including vagina, urethra, anus, clitoris.
º Lymphatic spread to regional lymph nodes can occur early even in women with small lesions. Most vulvar cancers spread initially to the superficial inguinal lymph nodes and then through to the deep femoral lymph nodes, followed by the pelvic lymph node chains. Lesions that are well-lateralized generally spread only to ipsilateral lymph nodes. Carcinomas of the clitoris or Bartholin glands can occasionally spread directly to the deep femoral and obturator lymph nodes, though this is rare in the absence of evident superficial inguinal lymph node involvement.
º The vulva is supplied by a rich network of lymphatics thus the risk of lymph node metastases is common. Risk of lymph node metastases increases with depth of stromal invasion. The risk of lymph node metastases in patients with <1 mm invasion is 3.1% versus 31% in patients with an invasion of 4 mm or greater (Table 20-1).
º Clinical evaluation of the groin nodes is inaccurate with more than 20% of palpably enlarged groin nodes ultimately histologically negative, and conversely approximately 20% of patients with clinically uninvolved groin nodes having pathologic evidence of groin metastases.2,3
º The presence of pelvic nodal metastases is rare in patients without clinically suspicious groin nodes or three or more positive uniteral groin nodes.4,5 It is also uncommon to observe metastases to the contralateral groin or to the deep pelvic nodes without ipsilateral groin metastases.
º Hematogenous dissemination can occur, but generally late in the course of the disease, and is rare in patients without inguinofemoral involvement.
• The posterior vaginal wall along the upper third of the vagina is the most common site of presentation. Lesions of the mid-vagina are uncommon.
• Vaginal tumors can invade locally to involve the paravaginal tissues, bladder, urethra, rectum, and pelvic wall. If biopsies of the cervix or vulva are positive, the tumor cannot be characterized as a primary vaginal cancer.
• Lymphatic spread is determined by the location of the primary tumor. For apical lesions, drainage is primarily to the obturator and hypogastric nodes and then to para-aortic lymph nodes. Lesions in the distal third of the vagina drain initially to the inguinofemoral lymph nodes. However, due to the complexity of the lymphatic system, any of the nodal groups may be involved.
• Hematogenous metastases occur late in the course of the disease and most commonly include lungs, liver, and bone.
• Invasive carcinoma of the cervix can grow as exophytic tumors protruding from the cervix into the vagina or as endocervical lesions causing expansion of the cervix with a relatively normal appearing surface.
• Cervix cancer can spread by direction extension into the low uterine segment, vagina, paracervical tissues by route of the broad and uterosacral ligaments, peritoneal cavity, bladder, or rectum. Extension into the ovaries is rare.
• In advanced disease, tumor may become fixed to the side wall by direct extension or from nodal involvement.
• Lymphatic spread of cervical cancer usually follows an orderly progression spreading first to the primary echelon nodes in the pelvis then to the para-aortic nodes, and then to distant sites. It is rare for para-aortic nodes to contain the first draining nodes.
• The risk of pelvic lymph node metastases increases with increasing depth of cervical invasion.6,7
• The most frequent sites of distant metastases are extrapelvic lymph nodes, lung, liver, and bone.
• The median age of diagnosis of uterine cancer in the United States is 61 years.8
• There are two types of endometrial carcinomas:
º Type I endometrial cancers are most common and account for approximately 70% to 80% of endometrial carcinomas. They are usually low grade with a generally favorable prognosis. They may be preceded by an intraepithelial neoplasm (atypical and/or complex hyperplasia) and are estrogen dependent.9
º Type II account for 10% to 20% of endometrial carcinomas. Histologies include grade 3 endometrioid carcinoma, serous, clear cell, squamous, mesonephric, undifferentiated. They are not necessarily associated with estrogen stimulation and occur in women who are older and postmenopausal. Prognosis is worse than with type I.
• Risk factors for disease include obesity, unopposed estrogen exposure, and tamoxifen.10–12
• Although endometrial cancer is most commonly sporadic, there are some genetic syndromes associated with increased risk of endometrial cancer including hereditary nonpolyposis colorectal cancer syndrome or Lynch syndrome, which is an autosomal dominant cancer susceptibility syndrome.13,14
• The main route of spread of endometrial cancer is lymphatic dissemination.
3. DIAGNOSIS AND STAGING
3.1. Signs and Symptoms
• The most common presentation is an ulcer, plaque, or mass on the labia majora. Labia minora, clitoris, mons, and perineum are less commonly involved. Pruritus is also a common symptom associated with vulvar disease. Vulvar bleeding or discharge, dysuria, and an enlarged lymph node are less frequent symptoms.
• Pelvic pain may be associated with advanced disease.
• The most common presenting symptom is abnormal bleeding.
• Other symptoms on presentation include malodorous discharge, mass, pain, dyspareunia, urinary (dysuria, hematuria, frequency) or gastrointestinal symptoms (tenesmus, constipation), and pelvic pain.
• The most common symptoms at presentation are abnormal vaginal bleeding, discharge, and postcoital bleeding.
• Patients with early-stage cervical cancer may be asymptomatic. Patients with advanced disease may present with pelvic or lower back pain.
• Bowel or bladder symptoms such as dysuria, incontinence, urgency, hematuria or pelvic pressure suggest advanced disease.
• The most common symptom at presentation is postmenopausal vaginal bleeding.
3.2. Physical Examination
• In addition to a history and physical examination, a complete pelvic examination and examination of the groins is mandatory.
• Careful examination of the vulva should be performed to determine the dimensions, distance from major midline structures including clitoris, anus, and urethral meatus.
• Approximately 5% of patients can have multifocal lesions, and a thorough examination of the perineum, anus, cervix, and vagina is required.
• Groins should be examined carefully as well in the supine position.
• A history and physical examination in addition to a complete pelvic examination of the pelvis is mandatory.
• Cystoscopy and proctoscopy should be performed if there is clinical suspicion for advanced disease.
• Special attention should be paid to the size, location, and extent of the tumor and whether there is invasion into the paravaginal tissues and/or pelvic side wall.
• In addition to a complete history and physical examination, careful pelvic examination should be performed. This should include an assessment of the external genitalia, vagina, and cervix.
• Speculum examination should take note of the appearance of the cervix, size and extension of the tumor on the cervix, and visual appearance of the mucosal surfaces of the vagina. Digital examination of the vagina should also note any mucosal irregularities.
• Bimanual examination should also be performed to assess the size and shape of the uterus as well as its position (anteverted/retroverted/axial), flexion (retroflexed/anteflexed), and presence of masses. Adnexa should be palpated for any tenderness or masses.
• Rectovaginal examination should also be performed to assess size of the tumor/cervix and extension into paracervical tissues. Note should be made of the mobility of the tumor, any nodularity, and distortion of the anatomy.
• Cystoscopy and proctoscopy should be performed if there is clinical suspicions for bladder or rectal invasion.
• Palpation of the groins as well as the supraclavicular fossa should be performed particularly in those patients with lower vaginal extension or advanced disease.
• Intravenous pyelography and radiography of the chest are the only imaging studies allowed to impact a patient’s cancer stage according to the FIGO cancer staging system. However, these studies have largely been replaced by computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET).15
• For patients with larger tumors (≥2 cm), clinically palpable inguinal adenopathy, or suspected metastases, anatomic imaging of the abdomen and pelvis is appropriate. CT and MRI are equally effective at detecting positive lymph nodes with moderate sensitivity and specificity.16
• MRI is superior to CT, physical examination, and ultrasound in the evaluation of the extent of local disease spread including tumor size, depth of stromal invasion, and vaginal or parametrial extension in most gynecologic cancers.17 Figure 20-5 demonstrates vaginal extension in a patient with locally advanced cervical cancer.
• 18F-fluorodeoxyglucose (FDG)-PET/CT has been shown to be superior to CT and MRI for detecting lymph node metastases in cervical cancer, and posttreatment residual FDG avidity on PET significantly predicts cause-specific survival.18–20 It is particularly useful in detecting para-aortic lymph node metastases in patients with cervical cancer and can be useful for determining the extent of external beam radiotherapy fields and for delineating the para-aortic nodal boost in this region (Fig. 20-6).21 Its use can be extrapolated to other gynecologic malignancies including vulvar and vaginal cancer. Although it has been less studied in other gynecologic malignancies such as vulvar and vaginal cancer, its use may also be appropriate given the similar natural history and epidemiology.
FIGURE 20-5. Patient with locally advanced cervical cancer with vaginal extension. Water-based lubricant is inserted into the vagina to aid in visualization of the extent of disease (green arrow). The white arrow denotes a fibroid in the uterus.
FIGURE 20-6. FDG-PET/CT on a patient with cervical carcinoma and FDG avid para-aortic and common iliac lymph nodes (contoured in orange).
• Anatomic imaging preoperatively for uterine cancer is generally not necessary if surgery is planned unless there is a suspicion for metastatic disease. In a rare patient for whom surgery is not planned, MRI is superior to CT for evaluating extent of myometrial invasion.22 For patients with uterine sarcoma or papillary serous histologies, anatomic imaging may be indicated to assess for metastatic disease.
4. PROGNOSTIC FACTORS
• Lymph node status: One of the strongest predictors of prognosis is inguinal lymph node status.5
• Predictors for nodal metastasis: Tumor size, depth of invasion, tumor thickness, and the presence or absence of lymphovascular invasion all contribute to risk of lymph node metastases.
• Margin status: Incidence of local failure has been found to be higher with margins of <8 mm in the primary resected vulvar specimen.23
• Stage is probably the most important prognostic factor for disease outcome.24–26
• Size: The prognostic importance of lesion size is controversial with several investigators noting a correlation with local recurrence, while others not.24–27
• Age: Age has been found to be an important prognostic factor in several studies with survival lower in patients above 60 years of age.24,28
• Location: The importance of disease location is controversial. Several investigators have noted improved survival for patients with disease located in the upper vagina compared to lesions in the distal vagina or involving the entire vagina.24,28,29
• Lymph node involvement is one of the most important predictors of outcome with number, size, and location also influencing overall survival.30,31
• Lymphovascular space invasion is associated with a higher risk of recurrence independent of lymph node involvement.32,33
• Tumor size is one of the most important predictors of local recurrence and overall death from cervical cancer whether treated with radiotherapy34,35 or surgery.36,37
• Anemia: Low hemoglobin either pretreatment or during radiotherapy has been associated with poor prognosis.38,39
• Overall treatment time: Prolongation of overall treatment time has been shown to result in significantly decreased survival with radiotherapy.40
• Age: Women who are younger at diagnosis have a lower risk of recurrence.41
• Stage is the primary determinant of prognosis and recommendation for adjuvant therapy.
• Histology: Serous carcinomas have historically been considered to be more aggressive neoplasms even in the absence of myometrial invasion. Endometrioid type particularly stage I have an excellent overall prognosis.
• LVSI: The presence of lymphatic invasion may be important particularly in unstaged, early endometrial cancer. However, its prognostic significance may be reduced in well-staged node-negative patients.
• Grade: The degree of differentiation may indicate tumor spread with higher rates of pelvic and para-aortic lymph node metastases as grade becomes less differentiated (Tables 20-2 and 20-3).42,43
• Pelvic Washings: The prognostic significance of positive pelvic washings is unclear particularly when it is the only evidence of disease outside of the uterus.44,45
• Lymph Node: Lymph node involvement particularly in the para-aortic region is associated with poorer prognosis.46
• Depth of Myometrial Invasion: The risk of lymph node metastases increases with the depth of myometrial invasion.42 Deep myometrial invasion is also correlated with a higher probability of extrauterine disease, treatment failure, and recurrence.
5. GENERAL MANAGEMENT
5.1. Vulvar Cancer
5.1.1. Surgical Management
• Small, minimally invasive tumors with <1 mm invasion beyond the superficial basement membrane have a very low (<1%) risk of regional lymph node metastases and can be treated with wide local excision alone.47 Any tumor that invades deeper than 1 mm beyond the most superficial basement membrane necessitates treatment of the regional nodes.
• Historically, surgical management of vulvar cancer consisted of en bloc resection of the vulva and inguinofemoral nodes which was associated with high rates of morbidity. Surgical excisions that remove less of the vulva and surrounding tissues are now more commonly used.48
• Radical local excision or radical partial vulvectomy is used to treat early-stage lesions. The excision should be taken down to the inferior fascia of the urogenital diaphragm; a 1 cm tumor-free margin has been shown to decrease the risk of local recurrence and should be the goal unless doing so would compromise function of a major organ.23
• An inguinal femoral lymph node dissection is performed for all lesions greater than stage IA. The standard approach has been a radical lymphadenectomy that removes both the superficial and deep inguinofemoral lymph nodes, however, sentinel lymph node biopsy is under investigation as an alternative to reduce the morbidity.49
• For lesions that are well-lateralized (>1 cm from midline structures) and do not involve the anterior labia minora, a unilateral lymph node dissection may be performed. In a prospective GOG study, only 2.5% of 272 patients with non-midline vulvar tumors were found to have contralateral groin node metastases in the absence of ipsilateral lymph node metastases.47 A bilateral lymph node dissection should be performed if lymph node metastases are found on unilateral dissection.
• Pelvic nodal dissection is generally not performed due to the associated morbidity of the procedure. The current standard of care is to administer pelvic radiation therapy in the presence of regional nodal disease.
5.1.2. Postoperative Radiotherapy
• Adjuvant radiotherapy for positive nodes is recommended when there are two or more microscopically positive lymph nodes, one or more macroscopically involved lymph nodes, any evidence of extracapsular extension, or if only a small number of lymph nodes was sampled. Postoperative radiotherapy may also be considered when margins are <10 mm or in patients with small tumors for whom an inguinofemoral lymph node dissection is prohibited.
• GOG 37, which randomized patients to adjuvant pelvic and groin radiotherapy versus pelvic lymph node dissection, was stopped early due to a significant relapse-free survival between the two treatment arms at 2 years.50 At 6 years, there was no significant difference in overall survival in the entire population (P = 0.18) that may be attributed to the greater number of intercurrent deaths in the radiotherapy arm. There was a significant overall survival advantage with radiotherapy in the subgroup of patients with fixed or ulcerated nodes or two or more positive lymph nodes. As a result, pelvic lymph node dissection in patients with vulvar cancer is rarely performed with regional nodal radiation now being the standard of care for patients with metastases to two or more groin nodes.
• For patients with close or positive surgical margins, re-excision should be considered. If re-excision is not possible, postoperative radiotherapy has been shown to decrease risk of local recurrence.51
• For patients receiving postoperative radiotherapy for positive groin nodes, radiotherapy fields should include bilateral groins and the caudal external iliac lymph nodes on the ipsilateral side.
• In the absence of clinical or radiographic evidence of pelvic lymph node disease, the superior border of the radiotherapy fields should encompass the caudal external iliac nodes and should generally not extend more cephalad than the middle of the sacroiliac joints.
• Radiotherapy to the primary tumor is generally recommended in most cases requiring radiation of the inguinal and pelvic lymph nodes. Risk of recurrence in tissues shielded by a midline block has been reported after postoperative radiotherapy.52
5.1.3. Preoperative Radiotherapy
• Preoperative radiotherapy is often considered when tumors approximate normal tissues such as the anal sphincter, clitoris, clitoral hood or frenulum, pubic arch, or with disease involving more than the distal urethra or extending past the vaginal introitus.
• Moderate doses of preoperative radiotherapy followed by surgical excision of the residual tumor have resulted in pathologic responses in approximately 50% of cases.53–55
• In a phase II study by the GOG, 71 patients with FIGO stage III or IV disease were treated with preoperative radiotherapy and chemotherapy delivered in a split-course regimen.56 Two patients had persistent unresectable disease; bowel and bladder continence preservation was achieved in all but three patients.
5.1.4. Definitive Chemoradiotherapy
• Definitive chemoradiotherapy may be considered for those for whom radical excision would require an ostomy as a result of bowel or bladder resection or for those with disease fixed to the bone. If residual disease remains after chemoradiotherapy, surgical excision is recommended.
• Although the studies are limited, the results have been reasonable with high rates of pathologic (70%) and clinical (48%) complete response (Table 20-4).57–64
• Treatment fields and doses are individualized. Due to the potential for enhanced late normal tissue effects due to the treatment of the vulva/skin, one should not exceed doses of 54 Gy in 30 fractions, 59.4 Gy in 35 fractions, or 64 Gy in 40 fractions to gross disease when chemoradiotherapy is used.
• Treatment fields should take into account the presence of normal tissues nearby including femoral necks, small bowel, bladder, urethra, anus, rectum, and urethra. One technique for treatment is the simultaneous use of a wide anterior low-energy photon field (4 or 6 MV) encompassing the entire target volume area including the perineum, groins and pelvic lymph node targets, and vulva, and a narrow high-energy (10 to 16 MV) posterior field to encompass the perineum and pelvic nodes while shielding the femoral necks. Anterior electron fields are then used to supplement the dose to the groins.
• Intensity-modulated radiation therapy (IMRT) may reduce the dose to normal tissues including small bowel, bladder, and rectum, and reduce treatment-related toxicity.65 (See section on IMRT.)
• Treatment of primary vaginal cancer should be individualized based on size, location, and stage of disease. Stage I lesions that are located in the upper vagina may be treated surgically with an upper vaginectomy, radical hysterectomy, and bilateral pelvic lymphadenectomy. Lesions that are in the mid to lower vagina or that approximate nearby organs including the urethra, bladder, or rectum are typically treated with radiation.
5.2.1. Primary Radiation therapy
• Small superficial lesions <2 cm in diameter may be treated with brachytherapy alone or surgery. If brachytherapy is used, surface doses of 90 to 100 Gy are used to treat apical lesions. For mid or distal lesions, tumor doses of 80 to 85 Gy are used with intracavitary or interstitial implant depending on the thickness of the residual tumor at implantation.
• Lesions >2 cm or stage II or greater require pelvic radiation therapy for treatment of the regional lymphatics. For tumors of the apical vagina, the fields should include the true pelvis with at least a 4 cm distal margin on the primary vaginal tumor which can be demarcated by gold seeds. If the vaginal tumor involves the distal third of the vagina, then inguinofemoral lymph node irradiation is indicated. Pelvic radiation doses of 40 to 50 Gy are usually required followed by an intracavitary or interstitial implant.
• Brachytherapy should be individualized based on the size, location, and extent of the tumor. Lesions that are <5-mm thick may be treated with a vaginal cylinder. For larger tumors, combination interstitial and intracavitary brachytherapy should be considered.
• The total dose of radiation to the tumor ranges from 75 to 85 Gy depending on the tumor size and extent of disease if brachytherapy can be delivered in conjunction with pelvic radiotherapy. If the location and extent of disease precludes brachytherapy, total tumor doses of 60 to 66 Gy should be delivered.
• Risk of complications are higher for vaginal cancers compared to cervical cancers with 10% to 15% of patients developing treatment-related complications including radiation cystitis, rectovaginal or vesicovaginal fistula, radiation proctitis, and vaginal necrosis.
• The use of chemotherapy in vaginal cancers in conjunction with pelvic radiotherapy for locally advanced vaginal cancers has been reported in several small series and its benefits in high-risk patients has been extrapolated from the randomized studies in patients with cervical cancers.66,67
• Primary treatment is total hysterectomy and bilateral salphingo-oophorectomy with or without lymph node dissection. The role of lymphadenectomy in women with early-stage disease is controversial as studies have demonstrated no therapeutic benefit to nodal dissection in this population, though there were methodological flaws in these studies.68,69 Some gynecologic oncologists advocate a risk-based approach with nodal dissection reserved only for patients at high risk of lymph node metastases.70
5.3.2. Adjuvant Treatment for Early-/ Intermediate-Risk Disease
• The role of adjuvant therapy in women with low- or intermediate-risk endometrial cancer is very controversial. Figure 20-7 demonstrates the current National Comprehensive Cancer Network (NCCN) recommendations for adjuvant therapy in this population. Women with grade 1 or 2 disease confined to the endometrium have a very low risk of recurrence. All other patients with stage I or II disease are generally considered at intermediate risk with definitions varying based on individual studies.
• Several randomized controlled trials of adjuvant radiation have been performed in women with intermediate-risk endometrial cancer (see Table 20-5). The use of pelvic radiation reduces the risk of local recurrence, however, does not impact overall survival.71–74 After 10 years of follow-up, there was no difference in overall survival between patients receiving pelvic radiotherapy versus observation in the Postoperative Radiation Therapy for Endometrial Cancer (PORTEC)-1 trial which randomly assigned women with stage IB grade 2–3 or stage IC grade 1–2 tumors to observation or whole-pelvic radiotherapy.71 The risk of vaginal recurrence was reduced from 15% to 4%.
• Given that two-thirds of recurrences in women with intermediate-risk disease occur in the vagina and to avoid the late morbidity of pelvic radiotherapy, vaginal cuff brachytherapy is now widely used to reduce the risk of vaginal recurrences (Table 20-6). Vaginal brachytherapy versus pelvic radiotherapy was investigated in PORTEC-2 in women with intermediate-risk disease.74 No difference in survival was demonstrated between the two methods, though there was a significantly higher risk of pelvic recurrences (3.8% vs. 0.5%) with vaginal brachytherapy.
• Various fractionation schemes can be used for delivering adjuvant high dose rate brachytherapy to the vaginal cuff with dose prescribed either to the vaginal surface or 0.5 cm.75 A common scheme is three fractions of 7 Gy delivered at 1-week intervals prescribed to 0.5 cm depth. The doses with low dose rate brachytherapy range from 60 to 70 Gy over 72 hours prescribed to the vaginal surface.
• The high rates of distant failure, particularly in women with high-risk features including grade 3 and deep myometrial invasion, have prompted studies investigating the use of adjuvant chemotherapy in uterine-confined disease. The use of adjuvant chemotherapy in addition to pelvic radiation has been examined in two studies of women with intermediate-risk endometrial cancer.76 The European Organization for Research and Treatment of Cancer and the Nordic Society of Gynecological Oncology reported results from a randomized study comparing adjuvant pelvic radiation versus chemotherapy (various regimens) and pelvic radiation in patients with stage I–III disease. The results demonstrated a progression-free survival benefit favoring combined chemoradiotherapy with a hazard ratio of 0.64 (95% CI: 0.41–0.99). The Japanese Gynecologic Oncology Group compared pelvic radiotherapy and chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in women with stage IC*–IIIC disease and found overall survival to be equivalent.77 However, a survival advantage was noted in the group of women whom they described as high to intermediate risk (stage IC*, >70 years of age, or grade 3; or stage II or positive cytology with >50% myometrial invasion). There are several ongoing studies of chemoradiotherapy versus radiotherapy in this group of women including Gynecologic Oncology Group protocol 249, which compares pelvic radiotherapy with vaginal brachytherapy plus carboplatin and paclitaxel chemotherapy, and PORTEC-3, which compares pelvic radiotherapy with radiation therapy plus chemotherapy for women with intermediate- and high-risk disease.1
FIGURE 20-7. NCCN flowchart for adjuvant treatment of endometrial cancer. Note that adjuvant therapy determinations are made on the basis of pathologic findings. This chart is taken from panel ENDO-4 of the National Comprehensive Cancer Network (NCCN) guidelines for uterine neoplasms, version 3, copyright 2012, and reproduced here with permission. The reader is encouraged to consult the full guidelines which contain more details (and other flow charts) for disease staging and management, including surgery and chemotherapy.
5.3.3. Adjuvant Therapy for Locally Advanced Disease
• Chemotherapy has become the mainstay of treatment in stage III and IV disease. A study of whole abdominal radiotherapy versus chemotherapy with cisplatin and doxorubicin in stage III and IV disease demonstrated the superiority of chemotherapy to radiation. The use of radiotherapy, however, in this group of women is currently undefined. Gynecologic Oncology Group study 258 is currently ongoing with patients randomized to carboplatin and paclitaxel with or without volume-directed radiation. Retrospective studies, however, have demonstrated an improved survival with combined adjuvant chemotherapy and radiation compared to either modality alone.78
• Pelvic radiotherapy may be delivered using a four-field box technique to reduce dose to small bowel. Doses of 45 to 50 Gy are customarily delivered to eradicate microscopic disease. IMRT may be used in this setting, particularly when chemotherapy is also being delivered to reduce the bone marrow dose.
• If para-aortic lymph nodes are involved, the fields can be extended to T11 or T12 vertebrae to ensure optimal coverage of perirenal nodes that may be at risk for direct spread via the tubo-ovarian vessels. Four fields can be used to reduce dose to the kidney; IMRT can also be considered to reduce the dose to bone marrow and small bowel. Doses of 45 to 50 Gy can be used to control microscopic disease.
• Radical hysterectomy is generally the preferred treatment for early-stage cervical cancer (FIGO stage IB1 or less), particularly in younger women as ovarian function and vaginal length can be maintained. However, patients with IB1 with high-risk features may require postoperative radiation therapy.
• For patients with IB2 disease, radical hysterectomy followed by postoperative radiotherapy ± chemotherapy or primary radiotherapy with concurrent chemotherapy can be administered.
• Patients with stage IIB or higher are generally treated with radiotherapy and concurrent chemotherapy.
5.4.2. Surgical Management
• Stage IA1 is usually treated with extrafascial hysterectomy which is considered the standard of care with cure rates approaching 100%. Conization may be appropriate for patients who desire to preserve fertility and do not have other high-risk features such as lymphovascular invasion which may indicate a higher incidence of lymphatic involvement.
• Patients with stage IA2 disease are not candidates for conservative treatment particularly if there is lymphovascular invasion present. Type II radical hysterectomy and pelvic lymphadenectomy is the recommended treatment with radiotherapy also an option.
• Stage IB1 and select IIA1 tumors without extensive vaginal involvement may be treated with radical hysterectomy and pelvic lymph node dissection. Radical hysterectomy involves the removal of the uterus, parametrial tissue, cervix, and upper vagina en bloc. Lymphadenectomy typically includes removal of the nodal groups that drain the cervix including the external, internal, and common iliac lymph nodes. Most clinicians will also remove the para-aortic lymph nodes.
• Posthysterectomy indications for radiotherapy alone include two or more of the following risk factors (capillary lymphatic space involvement, middle third or greater stromal invasion, or tumor ≥4 cm).79,80Addition of chemotherapy to radiotherapy is indicated for patients with positive lymph nodes, positive parametrial involvement, or positive margins.87
• For patients with stage IB and selected IIA disease, radical hysterectomy and pelvic lymph node dissection and primary external beam radiotherapy combined with brachytherapy have similar outcomes.64 In a randomized study by Landoni et al., radical hysterectomy was compared to primary radiotherapy in patients with stage IB–IIA disease. Of the patients who received initial surgery and had tumors >4 cm, 84% required postoperative radiotherapy and had more complications than those patients who had primary radiotherapy alone.
• For patients with stage IB2 disease, primary radiotherapy is an effective treatment with a 90% local control rate.34,81 Some oncologists prefer radical hysterectomy for these patients, however, the majority will require adjuvant radiotherapy with or without chemotherapy.64
• The GOG found no benefit to extrafascial hysterectomy for women with bulky stage IB cervical carcinoma after primary radiotherapy.82
• For patients receiving radiotherapy in the definitive setting, the treatment fields should encompass the whole pelvis using a four-field, two-field, or IMRT technique (see IMRT section). If using a four-field technique, care should be taken to avoid blocking areas of potential disease. The whole pelvis should be treated to a dose of 40 to 45 Gy in 20 to 25 fractions. Brachytherapy is a critical component to therapy for intact cervical cancer and should be delivered in conjunction with external beam radiotherapy. An additional 40 to 45 Gy to the tumor either with low dose rate brachytherapy or the biologically equivalent dose with high dose rate brachytherapy should be delivered.
• Patients who have positive para-aortic lymph nodes should be treated with extended field radiotherapy. The upper border should be extended to the T12 vertebral body. The upper portion of the field can be treated with IMRT (see below) or with four-field conformal radiotherapy to reduce the dose to the kidneys and small bowel. Lymph nodes should be boosted doses of 55 to 60 Gy. Microscopic disease should be treated to 45 to 50 Gy.
5.4.4. Radiotherapy and Chemotherapy
• The results of five prospective randomized studies in women with cervical cancer receiving definitive radiotherapy with or without cisplatin-based chemotherapy or adjuvant radiotherapy with or without cisplatin-based chemotherapy demonstrated significantly improved rates of overall survival, disease-free survival, and local control with chemotherapy (Table 20-7).83–87 The results of these trials culminated in the National Institutes of Health alert changing the standard treatment for locally advanced cervical cancer to concurrent chemoradiotherapy.
• A subsequent meta-analysis that included 15 randomized controlled studies that included a total of 3,452 patients confirmed that the addition of concurrent chemotherapy to radiation therapy in women with cervical cancer improved both progression-free and overall survival.88
• Several randomized studies have investigated radiotherapy alone versus radiotherapy and non-cisplatin-containing regimens including 5-fluorouracil, mitomycin, and gemcitabine.89–91 Most recently, Duenas-Gonzalez et al. have published results of a phase III randomized study of concurrent gemcitabine and cisplatin chemoradiotherapy plus adjuvant gemcitabine and cisplatin compared to concurrent cisplatin chemoradiotherapy in patients with stage IIB–IVA cervical cancer. Patients receiving the gemcitabine-containing regimen had superior overall survival (HR: 0.68; 95% CI: 0.48–0.95) and progression-free survival (HR: 0.68; 95% CI: 0.49–0.95). Toxicities were more frequent with the gemcitabine-containing regimen (86.5% vs. 46.3%, respectively, P < 0.001).90
• Studies examining neoadjuvant chemotherapy have been performed with mixed results.92–95 In a randomized study by Tang et al., neoadjuvant chemotherapy with paclitaxel (135 mg/m2) and cisplatin (75 mg/m2) prior to concurrent chemoradiation followed by two cycles of consolidation chemotherapy was compared to standard concurrent chemoradiation with weekly cisplatin chemotherapy. They found a significantly longer disease-free and cumulative survival with higher rates of locoregional control with neoadjuvant and adjuvant chemotherapy.92 Others have found no difference in overall survival with neoadjuvant chemotherapy.93,94,96,97
6. INTENSITY-MODULATED RADIATION THERAPY
• Intensity-modulated radiation therapy (IMRT) in the female pelvis is most frequently used in the posthysterectomy setting either for operative cervical cancer or endometrial cancer. It is also increasingly used for vulvar cancer to help reduce the dose to the small bowel, bladder, and rectum. Several studies have demonstrated the superiority of IMRT for reducing the small bowel dose with whole-pelvic radiotherapy.98,99 For treatment including the groin region with vulvar cancer or lower vaginal involvement of cervical or vaginal cancer, IMRT has been shown to reduce the dose to the bladder, rectum, and small bowel as well.
6.1. Target Volume Delineation: Posthysterectomy
• In the posthysterectomy setting, the clinical target volume (CTV) should include all regions of gross or microscopic disease which would include the regional nodes, parametrium, and upper half of the vagina (Fig. 20-8).
• The regional lymph nodes include the bilateral obturator, external and internal iliac, and common iliac nodes. For patients with cervical cancer or involvement of the cervix in endometrial cancer, the presacral region should also be included extending to S3 to ensure coverage of the presacral lymph nodes and uterosacral ligaments. For patients with lower vaginal disease or vulvar cancer, bilateral inguinofemoral nodes would be included.
• All lymphoceles should be contoured and included in the CTV as well.
• The CTV is enlarged by 7 to 10 mm to create the planning target volume (PTV) to account for setup uncertainty and organ motion. Margins may be lower if daily image-guided radiotherapy (IGRT) is used. Conversely, for patients who are obese and on whom IMRT is used, margins may need to be more generous particularly in the absence of IGRT.100
FIGURE 20-8. Axial views of contours of a patient treated with adjuvant IMRT after hysterectomy for endocervical adenocarcinoma. Small bowel (green), rectum (brown), bladder (yellow), CTV nodes (red), and CTV vagina (orange).
• Several studies have reported that the vagina can move substantially during the course of pelvic radiotherapy.101–103 Ma et al.102 in a study of 11 patients with cervical or endometrial cancer posthysterectomy who underwent gold seed fiducial placement prior to simulation found the maximal vaginal cuff movement in any direction to be 34.5 mm using daily megavoltage CT imaging. The mean displacement in the axial and craniocaudal direction was 12.9 ± 6.7 mm and 10.3 ± 7.6 mm, respectively. As a result, simulation with the bladder empty and full and creating a vaginal internal target volume (ITV) can better approximate vaginal motion. Margins of 2 cm may be appropriate.
6.2. Target Volume Delineation: Intact Cervical Cancer
• There is considerable controversy regarding the use of IMRT for intact cervical cancer given the considerable organ motion and tumor regression that occurs over the course of radiotherapy.104–106
• Beadle et al.105 in a study of 12 patients with cervical cancer who received pre-, weekly, and post-CT imaging during conventional chemoradiotherapy found that mean cervical tumor volume regression was 62.3%. They found that the maximal changes in the perimeter of the cervix were in the superior–inferior and anterior–posterior direction, 2.3/1.3 and 1.7/1.8 cm, respectively.
• The GYN IMRT Consortium developed contouring guidelines for cervical cancer–based on MRI. The CTV includes the entire gross tumor volume (GTV) which is denoted by intermediate/high signal on T2 images, the entire cervix (if not already included in the GTV), entire parametria including ovaries, and the mesorectum of the uterosacral ligaments. If the vagina is uninvolved or minimally involved, the CTV should include the upper half of the vagina. If the upper vagina is involved, the CTV should include the upper two-thirds of the vagina, and if the vagina is extensively involved, the CTV should include the entire vagina.107 Figure 20-9 demonstrates the contours of a representative patient.
• Contours of the iliac and obturator nodal groups should follow the guidelines for posthysterectomy patients.
• Within the para-aortic region, the lymph nodes can be located several centimeters from the aorta and inferior vena cava. In a study by Chao and Lin., the lymph nodes on the left of the para-aortic region were located at a mean distance of 22.2 ± 12.2 mm from the aorta (range 10.3 to 44.5 mm).108 On the right side, the para-aortic nodes were found to be 9.1 ± 3.3 mm from the inferior vena cava (range 5.0 to 14.9 mm). Their recommendations were to place a 2-cm margin on the aorta and a 1-cm margin on the inferior vena cava and expand to include any lymph nodes ≥2 cm fully.
• Esthappan et al.21 have described simulation and treatment planning methods for 18F FDG-PET/CT–based IMRT for cervical carcinoma with positive para-aortic lymph nodes that resulted in decreased dose to the bowel volume and kidneys.
6.3. Target Volume Delineation: Vulvar Cancer
• IMRT is increasingly being used for vulvar cancer in the postoperative, preoperative, or definitive treatment setting.65,109
• Patients should be simulated in the frog leg position with careful attention to reduce the regions of overlapping skin.
• The regional lymph nodes include the inguinal femoral lymph nodes, bilateral external and internal iliac lymph nodes depending on the treatment situation.
• The primary vulva should also be included as part of the CTV. The primary vulva CTV should include the entire vulva and vagina, though there is considerable controversy regarding the delineation of target volumes for the primary vulva. For example, some physicians place a 1-cm margin on the CTV when the vagina is involved, whereas others consider the entire vagina at risk and include this in the CTV. Margins of 7–10 mm on the blood vessels to encompass the external and internal iliac nodes should be used. Within the inguinofemoral region, margins of up to 3 to 4 cm are needed on the inguinofemoral vessels.110 Contouring the entire compartment rather than constructing circumferential margins around the vessels in this region may more reproducibly cover the at-risk lymph nodes (Fig. 20-10A).
• Anatomic boundaries of the groin region are as follows: laterally, medial border of the iliopsoas; medially, the lateral border of the adductor longus or medial end of pectineus; anteriorly, the anterior border of the sartorius muscle; and posteriorly, the iliopsoas muscle and anterior aspect of the pectineus muscle (Fig. 20-10B). Kim et al.110 found that the majority of macroscopic nodes were medial or anteromedial to the femoral vessels. The caudal extent of the volume should be 2 cm inferior to the saphenous–femoral junction. The transition to the external iliac region is less defined, but the RTOG consensus panel contouring atlas for anorectal carcinoma recommends the caudal extent of the internal obturator vessels (upper edge of the superior pubic rami).111
FIGURE 20-9. Patient with stage IIIB cervical cancer with disease extending to the pelvic sidewall on the left. Pelvic MRI (panel B) was obtained at the time of simulation in treatment position and fused to the CT scan (panel A). Contours: bladder (yellow), rectum (brown), GTV (cyan), Modified parametrial volume (purple).
6.4. Normal Tissue Delineation and Constraints
• The normal tissues that should be delineated in the pelvis include the bladder, rectum, small and large bowel, and bone marrow (femoral heads and pelvic bones).
• Rectum should be contoured from the level of the anus to the sigmoid flexure. It should extend inferiorly from the anal verge (marked by a radiopaque marker at simulation) to superiorly where the rectum moves anteriorly and connects with the sigmoid.
FIGURE 20-10. Panel A: CTV of the primary and bilateral groins in a patient with T2N2 vulvar cancer. Panel B. Recommended boundaries for delineation of the inguinofemoral region. Pectineus muscle (yellow), iliopsoas muscle (blue), rectus femoris (purple), sartorius (green) adductor longus (dark green). (Based on recommendations in Kim CH, Olson AC, Kim H, Beriwal S. Contouring inguinal and femoral nodes; how much margin is needed around the vessels? Practical Radiat Oncol 2012;2(4):274–278.)
• The small and large bowel can be contoured together as a bowel bag as per normal tissue guidelines developed by the RTOG consensus panel atlas.112 Inferiorly, the bowel bag should begin with the first small or large bowel loop or above the anorectum, whichever is most inferior. The bowel bag contours should end 1 cm above the PTV if coplanar beams are used. If noncoplanar beams are chosen, the contours will need to extend further.
6.5. Results of IMRT
• In one of the initial dosimetric studies of IMRT for gynecologic malignancies, Roeske et al.98 reported that the average volume of small bowel receiving the prescription dose was reduced by a factor of 2 in patients receiving pelvic radiotherapy with IMRT versus standard three-dimensional conformal radiotherapy (3DCRT). The volume of bladder and rectum receiving the prescription dose was also significantly reduced. Figure 20-11 shows the isodose distributions for a representative plan.
• Mundt et al. reviewed the gastrointestinal toxicities observed in patients with cervical and endometrial carcinoma who received pelvic IMRT compared to conventional whole-pelvic radiotherapy. They found a significantly lower rate of grade ≥2 acute gastrointestinal toxicities in patients who received IMRT compared to conventional whole-pelvic radiotherapy (60% vs. 91%, P = 0.002).95 No patient developed grade 3 toxicity. There was less frequent grade 2 genitourinary toxicities observed in the IMRT group, however, this was not statistically significant (P = 0.22).
FIGURE 20-11. (A) Axial, (B) sagittal, and (C) coronal views of a typical IMRT plan for a patient receiving adjuvant 45 Gy whole pelvis radiotherapy after hysterectomy. Isodose lines: 50 Gy (red; small contour near center of A and B only) 45 Gy (yellow), 40 Gy (blue), 30 Gy (pink). PTV is cyan wash.
• In contrast, Jhingran et al.113 reported results of RTOG 0418 which was a phase II multi-institutional study of pelvic IMRT with or without chemotherapy after hysterectomy for patients with endometrial or cervical cancer. Overall, they found a 28% incidence of grade ≥2 bowel toxicities which was not significantly different from the 40% incidence observed in a historical group of patients who received standard whole-pelvic radiotherapy (P = 0.12), though they did note that their sample size was not sufficient to detect a 12% difference in grade ≥2 bowel toxicities.
• In one of the largest single-institution retrospective series comparing IMRT to standard whole-pelvic radiotherapy in patients with cervical cancer, Kidd et al.114 reported significantly lower rates of grade ≥3 bowel or bladder complications with IMRT. There was no difference in recurrence-free survival, though the IMRT group did have a superior cause-specific survival and overall survival (P < 0.0001).
• In an analysis by Shih et al.,115 results of pelvic IMRT for high-risk endometrial cancer were reported after hysterectomy with or without chemotherapy. Treatment was well-tolerated with two patients developing nonhematologic grade 3 toxicity, one acute, and one chronic gastrointestinal toxicity.
• In a dosimetric study of IMRT comparing 3DCRT in 15 patients with vulvar cancer treated in the preoperative or adjuvant setting, Beriwal et al.65 found that the mean volume of small bowel, rectum, and bladder receiving doses >30 Gy was lower in IMRT compared with 3DCRT (P < 0.05). Figure 20-12 demonstrates the isodose distributions for a representative plan.
FIGURE 20-12. IMRT plan of a patient with a T2N2 vulvar carcinoma. PTV is cyan wash. Isodose lines: 40 Gy (blue), 45 Gy (yellow), 50.4 Gy (orange), 47.8 Gy (green), 20 Gy (light blue).
• Beriwal et al. published their results of preoperative IMRT with concurrent chemotherapy, either cisplatin and 5-fluorouracil chemotherapy with twice daily radiotherapy or daily fractionated radiotherapy with weekly cisplatin chemotherapy in 42 patients. Median dose of radiation was 46.4 Gy. Pathologic complete response (pCR) rate in the vulva was 48.5% with 61.5% pCR in the inguinal region. There was no grade 3 desquamation in the groin region in any patient. There were no nodal recurrences in patients who had no clinically suspicious or enlarged lymph nodes and had no inguinal node dissection after chemoradiation.116
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* Based on 1998 FIGO Uterine Cancer Staging Criteria.