Embolization Therapy: Principles and Clinical Applications, 1 Ed.

Gynecologic Malignancies

Theresa M. Caridi • Richard Shlansky-Goldberg

BACKGROUND

In the United States in 2010, 83,745 womesn were diagnosed and 28,770 died from a gynecologic cancer.1 These include cervical, ovarian, uterine, vaginal, and vulvar cancers and the rare fallopian tube malignancy. In addition, these structures may be involved in metastatic disease from nongynecologic sources. Survival rates for nearly all cancers have improved significantly since the 1970s due largely to earlier detection and/or advances in treatment. Many gynecologic cancers are curable, and the mainstay of treatment remains a combination of surgery, radiation therapy, and chemotherapy. Staging and pathology ultimately determine the treatment type and whether individual or combination therapy is needed. In rare circumstances, embolization of gynecologic malignancies may be employed. These include the setting of life-threatening hemorrhage, preoperatively when there is a predisposition for massive bleeding, and rarely as a treatment of the cancer itself. Treatment of nonhemorrhagic gynecologic malignancy by endovascular methods is infrequent, not only because cure is often achieved by other methods but also because prior treatment with pelvic irradiation increases the risk for uterine necrosis after embolization. Regarding significant bleeding from primary or metastatic disease or as a complication of surgical or radiation therapy, endovascular treatment decreases morbidity and mortality as it is minimally invasive and generally more effective at rapidly achieving cessation of bleeding than surgery (Figs. 56.1 and 56.2).2

Cervical Cancer

The American Cancer Society estimates approximately 12,340 new cases and 4,030 deaths from invasive cervical cancer in 2013.3 Historically, cervical cancer was once one of the most common causes of cancer death for women; however, between 1955 and 1992, the cervical cancer death rate declined by almost 70% owing to the increased use of the Pap test. Cervical cancer is now highly preventable in most Western countries because of both Pap screening and more recently availability of a vaccine to prevent human papillomavirus infections. When found early, cervical cancer is highly treatable and associated with long survival and good quality of life. Treatment usually consists of surgery, radiation therapy, and chemotherapy. The role of embolization is limited due to early detection and curable disease, but it can be useful in the setting of advanced disease with chemoinfusion/embolization, hemorrhage, and also bleeding from a cone biopsy.

Ovarian Cancer

Ovarian cancer accounts for about 3% of cancers among women, but it causes more deaths than any other cancer of the female reproductive system.1 The American Cancer Society estimates approximately 22,240 new cases and 14,230 deaths from ovarian cancer in 2013.3 A woman’s risk of getting ovarian cancer during her lifetime is approximately 1 in 72, and her lifetime chance of dying from ovarian cancer is about 1 in 100, not including low malignant potential ovarian tumors. However, the rate at which women are diagnosed with ovarian cancer has been slowly falling over the past 20 years. The primary treatments for ovarian cancer include surgery, chemotherapy, hormone therapy, targeted therapy (such as bevacizumab), and radiation therapy. Often, a combination of treatments is enlisted. The role for embolization is limited, as combination therapy is often curative, or at least aimed at cure. Additionally, ovarian cancer historically has a low propensity to result in life-threatening hemorrhage.

Uterine Malignancy

The American Cancer Society estimates approximately 49,560 new cases and 8,190 deaths from cancer of the uterus in 2013.3 The death rate for uterine cancer, which was the leading cause of cancer death in the early 20th century, declined from 1930 to 1997 but has since been nearly stable. The grouping of uterine cancer includes both endometrial cancers and uterine sarcomas, with only 2% being uterine sarcoma. The four established methods of treatment for women with endometrial cancer are surgery, radiation therapy, hormonal therapy, and chemotherapy. Again, there is a limited role for embolization except in the setting of hemorrhage. Similarly, a malignancy involving but not originating from the uterus is gestational trophoblastic disease. Like those neoplasms noted earlier, these lesions may also cause uncontrollable bleeding.4

Vaginal and Vulvar Cancer

In 2010, there were 1,211 women in the United States diagnosed with vaginal cancer and 4,305 women with vulvar cancer.1 Vaginal and vulvar cancers are rare, accounting together for approximately 6% to 7% of all gynecologic cancers diagnosed in the United States. Deaths are also low in number, with 423 women in the United States in 2010 who died from vaginal cancer and 942 who died from vulvar cancer. Invasive vaginal and vulvar cancers are treated mainly with radiation therapy and surgery. Chemotherapy in combination with radiation may be used to treat advanced disease. As in other gynecologic malignancies aforementioned, embolization is not a mainstay of treatment apart from the setting of hemorrhage.

In the 1970s, early reports of transarterial embolization for gynecologic malignancy were published. Schwartz et al. reported seven patients, two of whom were bleeding from their malignancy itself and five from bleeding related to therapy.5,6 Four out of the seven patients had bleeding controlled with autologous clot embolization or balloon tamponade, whereas three failed who had bleeding treated with vasopressin. Following this, Athanasoulis et al.7 published the use of gelatin sponge to successfully treat bleeding from radiation used as therapy for two cases of cervical carcinoma. Miller et al.8 also published two cases with gelatin sponge to treat radiation-induced bleeding associated with gynecologic malignancies using a femoral approach in one and a brachial in another. Kelemen et al.9 along with Smith and Wyatt10 demonstrated the technique of bilateral anterior division internal iliac embolization with gelatin sponge for massive vaginal bleeding from pelvic malignancies. In the 1980s, embolization was described as a technique to control bleeding from gestational trophoblastic disease and as a preoperative technique to reduce intraoperative bleeding.11,12

More recently, with the use of microcatheters and permanent embolics such as coils and particles, embolization has become easier and safer; chemotherapy can be added to embolization procedures as well. Arterial infusion with or without embolics is being used to treat ovarian and cervical cancer. In the 1990s, embolization with intra-arterial infusion of chemotherapeutic agents was described.13 Twenty-two patients with advanced gynecologic cancer underwent embolization and infusion of cisplatin with a 73% response rate, allowing a large portion of patients to be surgically resected.

More recent reports with larger numbers of patients with advanced gynecologic cancers have been published, demonstrating the advantage of embolization over surgery in palliative care of patients with bleeding complications from their malignancy.2 Advances in the care of patients with cervical cancer with transuterine arterial chemotherapy have allowed for fertility-sparing management using arterial cisplatin and intravenous nedaplatin or irinotecan and vaginal trachelectomy.14 In addition, a phase II study of 22 patients using transuterine embolotherapy with cisplatin and Gelfoam sponges with intravenous chemotherapy demonstrated 5-year progression-free and overall survival rates in stages IB2 to IIB to be 70.0% and 69.5%, respectively. The 2 patients with stage IVA tumors were alive without recurrence for 72 and 84 months after enrollment.15

TECHNIQUE

The most likely use of embolization for gynecologic malignancies is in life-threatening hemorrhage and typically involves embolization of the hypogastric or uterine arteries and, less commonly but occasionally, the ovarian arteries. As with treatment of benign disease, there is variation in operator approach to embolization of the pelvic vessels. All are performed in an angiography suite equipped for digital subtraction angiography or in an operating room with similar equipment. The standard approach is right common femoral artery access followed by aortography with a nonselective flush catheter, particularly in the setting of hemorrhage. The flush catheter is positioned at approximately the L1 vertebral body level to allow for imaging of the ovarian arterial origins in addition to the pelvic flow. Selective and superselective catheterization can be performed with any of several 4-Fr or 5-Fr catheters, such as a Cobra, VS, Simmons, or Roberts Uterine Catheter (RUC) (Table 56.1). Many operators will switch to a microcatheter to select the uterine artery for embolization because it will allow greater flow and reduce the incidence of spasm. Others perform bilateral femoral punctures to reduce procedure and radiation time.16 Regardless of the suspected source of hemorrhage, bilateral angiography as well as embolization is often performed owing to the vast pelvic blood supply in uterine disease.

Ipsilateral catheterization is commonly performed with use of the Waltman loop technique but again can be performed by accessing the contralateral common femoral artery in a bilateral puncture approach. Waltman et al.17described looping of a catheter back over itself by selecting a suitable visceral vessel and pushing the catheter up into the aorta, with attention given to avoid damage to the visceral vessel of choice. Historically, this technique worked well with braided catheters; however, some operators suggest the newer hydrophilically coated 4-Fr and 5-Fr catheters are more susceptible to kinking while the Waltman loop is being formed. Also, these catheters have the tendency to uncoil while the loop is withdrawn into the ipsilateral iliac artery and risk dissecting a vessel while reforming the reverse shape.

Noting these limitations, Cope18 in 1986 described the catheter reversal maneuver with a suture, which eliminated the need to select a vessel to form a loop, thereby reducing the risk of dissection and atheroemboli. The technique was further refined for uterine artery embolization using a 4-Fr non–tapered angled glide catheter (Boston Scientific Corporation, Natick, Massachusetts) and more recently with the RUC.19 The suture technique involves threading 2 to 3 cm of 4-0 Tevdek II suture into the end of a catheter. Then, a 0.035-in wire is back-loaded into the catheter so that approximately 3 to 4 cm of wire remains outside the tip of the catheter. The friction of the suture and wire against the inner sidewall of the catheter allow the suture to remain tightly fixed to the tip of the catheter. The unit as a whole can then be introduced through a 5-Fr sheath (Fig. 56.3). The tip of the wire/suture/catheter combination is advanced high within the abdominal aorta, with the opposite end of the suture lying outside of the sheath. As the catheter is pushed into the sheath and the trailing end of the suture is simultaneously pulled, the catheter folds back on itself to form (Fig. 56.4). The wire can then be withdrawn, releasing the suture, which is simply withdrawn from the sheath. The catheter is withdrawn from the sheath to engage the ipsilateral common iliac, internal iliac, and ultimately the uterine artery if desired (Fig. 56.5). A coaxial microcatheter can be advanced into the horizontal segment of the uterine artery if indicated. Following ipsilateral embolization, the catheter is advanced into the aorta and pulled down into the contralateral iliac artery for treatment of the other side.

Both temporary and permanent embolic materials are available for occlusion. Permanent embolic agents such as particulate agents, metallic coils, plugs, and liquid embolics are typically required for hemorrhage from progressive malignant disease.20 Oftentimes, however, temporary agents such as absorbable gelatin sponge are used in conjunction with a permanent embolic. Vessel size, type of hemorrhage (focal or diffuse), end organ, and collateral supply dictate the embolic chosen. For example, particles are useful in diffuse arterial hemorrhage and coils are more effective for a focal arterial abnormality. With regard to particles, the level of vascular occlusion is controlled by the size selected. The particulates are not radiopaque and therefore are injected as a mixture with contrast material. Embolization should occur until marked pruning of the arterial tree is seen on postembolization angiography.

New liquid polymers are approved by the U.S. Food and Drug Administration for use in the central nervous system and are used infrequently in an off-label fashion in the pelvic vessels.20 Some authors do report durable occlusion of both small pelvic arteries and major inflow arteries with liquid embolics.

To deliver these embolics, the authors’ preference is single puncture access into the right common femoral artery, followed by advancement of the preloaded 5-Fr Roberts catheter with Tevdek suture. A microcatheter is typically used to access the horizontal segment of the uterine artery if desired before embolization is performed. Strategies and tips regarding this technique are discussed in the “Tips and Tricks” section.

CLINICAL APPLICATIONS

As previously mentioned, the most likely use of embolization for gynecologic malignancies is in the setting of massive genital bleeding related to uncontrolled tumor growth of advanced uterine cancer (whether cervical cancer, endometrial cancer, or uterine sarcoma) with parametrial and fornix infiltration.2 Massive genital bleeding is a serious complication, allowing for deterioration of the patient’s clinical status and a worse prognosis. In some cases, packing the vaginal canal is sufficient to tamponade the tumoral bleeding. These patients then go on to external radiotherapy. When this type of conservative approach is unsuccessful, endovascular or surgical therapy is needed. Embolization often involves hypogastric or uterine artery embolization, whereas surgical treatment can involve arterial ligation or hysterectomy.

Studies show pelvic uterine embolization is nearly bloodless, atraumatic, and more efficient when compared to surgery for massive bleeding. An additional benefit of endovascular treatment in the setting of bleeding gynecologic malignancy is it enables continuation of external radiotherapy without delay. Surgical management on the other hand is associated with significant morbidity and oftentimes a longer recovery without the ability to continue external radiotherapy. Surgery can also compromise desired fertility because of hysterectomy or oophorectomy. Furthermore, the reported efficacy of embolization for massive genital bleeding is as high as 90% and, if unsuccessful, does not preclude additional surgical intervention.

Two primary techniques are performed, depending on the patient’s clinical status. In the scenario of poor patient status and diffuse massive hemorrhage, embolization of the bilateral internal iliac arteries may be warranted.2 This can be accomplished rapidly by deploying coils within both internal iliac arteries. Another option is delivering permanent particles into the anterior division after protecting the posterior division with coil blockade. Recognizing that arterial branches not contributing to the hemorrhage may be sacrificed, some authors suggest proximal internal iliac artery coil occlusion with the premise that it will aid to quickly stop hemorrhage while releasing the distal microcirculation for eventual revascularization. This, however, may lead to failure due to collateralization and inability to offer any other endovascular solution. Rarely, access into the uterine arteries provides such difficulty that proximal embolization within the internal iliac arteries is necessary. This is sometimes seen with severe hypotension or shock and rarely with difficult arterial anatomy. In the alternate scenario where a patient’s clinical status is stable, superselective microcatheterization of the bilateral uterine arteries with superselective embolization can be performed.

There are no absolute contraindications to embolization for life-threatening pelvic hemorrhage in the background of gynecologic malignancy, whereas elective embolization should be avoided in those with previous pelvic irradiation, chronic kidney disease, pelvic infection, refractory coagulopathy, use of gonadotropin-releasing hormone analogues (due to uterine artery constriction), or intrauterine pregnancy with normal placental implantation.20

POTENTIAL COMPLICATIONS

Fortunately, complications of embolization for gynecologic malignancies are rare, with an incidence estimated at 6% to 9%.20 Complications can be separated into five major categories: those related to angiography, ischemia, thromboembolism, radiation, and drugs. Complications of basic angiography include access site bleeding/hematoma, vascular damage, and contrast reaction or nephrotoxicity. In the setting of uterine artery catheterization in particular, spasm of the uterine arteries can occur, requiring intra-arterial nitroglycerin to complete the planned embolization.

Although the intended result of embolization is ischemia, complications can occur from ischemic damage to the uterus and/or ovaries.20 Fortunately, they often have the capacity to recover. Pelvic pain is not uncommon following uterine artery embolization and is also related to ischemia. Fever and nausea are not uncommon and along with pain are part of a spectrum of postembolization syndrome. Nontarget embolization can occur as with any embolization procedure. The ovary is the organ most frequently affected due to the utero-ovarian vascular anastomoses. Premature menopause can also ensue when the ovarian supply is embolized, particularly if the patient is in the premenopausal state. Fertility following uterine artery embolization for gynecologic malignancy has not been discussed in the literature except for uterine fibroid embolization, in part because the procedure is performed rarely except in life-threatening hemorrhage and also fertility is unlikely to be a point of concern in women with advanced malignancy. Other nontarget embolization can occur with occlusion of adjacent branch vessels to the bladder or rectum, resulting in bladder/rectal necrosis or sexual dysfunction.

Deep venous thrombosis (DVT) and pulmonary embolism have been reported after uterine artery embolization, with one thought being stagnation and clotting of the venous drainage at least in part from blockage of the arterial inflow. Additionally, development of thrombus is common in the setting of malignancy due to hypercoagulable state, and if there is bulky pelvic disease, direct pressure can further result in compromised venous flow and the propensity to form DVT. Finally, patients with gynecologic malignancy are at times treated with hormonal therapy, also increasing the risk for DVT.

Angiography and embolization is performed under fluoroscopy, therefore women are exposed to radiation. Theoretically, prolonged angiography and embolization can lead to radiation burn to the skin, although no known cases have been found in the literature regarding uterine artery embolization. The amount of radiation to the ovaries varies widely depending on anatomy and operator experience; however, it is not expected to affect fertility and again is not usually of concern in advanced malignant disease.

Most embolization procedures are performed using moderate sedation with use of a short-acting intravenous narcotic and sedative, typically fentanyl and Versed. Allergic reactions can occur, although are atypical, and more common side effects include dry mouth and urinary retention. Medications can also result in oversedation; however, care is taken to administer sedation in small doses as needed. Reversal medications can also be employed if indicated. As with any procedure, there is always a risk of death related to one of the previously mentioned complications. In the setting of uterine artery embolization, the most likely cause of immediate death of those mentioned is pulmonary embolism.

TIPS AND TRICKS

For embolization of gynecologic malignancies via the uterine arteries, there are a few basic suggestions made by the authors to promote technical success and efficiency. An RUC with its long reversed curve tip makes catheterization rather quick and simple, especially when combined with the Cope suture technique (Fig. 56.6). A list of recommended materials can be seen in Table 56.1. A very basic suggestion is the use of a 5-Fr/15 cm transitionless sheath, which eliminates the conversion from micropuncture to 0.035-in system if a micropuncture system is used. Additionally, when the use of the authors’ technique is employed, this sheath allows for easy advancement of the Tevdek wire–loaded Roberts catheter. Otherwise, the RUC would need to be reshaped over the bifurcation.

Numerous other catheters can be used such as the cobra shape, but the RUC represents the authors’ preferences. In terms of selection of the common iliac artery, followed by internal iliac artery, anterior division of the internal iliac artery, and ultimately the uterine artery, we recommend specific positioning of the tip of the catheter to achieve easy, rapid, and safe catheterization. Initially, lateralizing the tip of the RUC to achieve catheterization of the common iliac artery followed by quickly changing to a posterior and medial tip position to select the internal iliac artery is standard opening technique. As the RUC is retracted (bringing the tip down deeper into the pelvis), the tip of the catheter should be turned in an anterolateral position in parallel to the external iliac artery to catheterize the anterior division of the internal iliac artery and subsequently the uterine artery. One gets accustomed to the deflected tip appearance as the RUC enters the origin of the uterine artery.

It may be difficult to catheterize the uterine arteries when they originate at an upgoing angle greater than 90 degrees relative to the inferior gluteal artery as the terminal branch of the anterior division. Useful catheters in this setting are the Roche inferior mesenteric (RIM), the tight-curve Binkert (TC-BNK), and the internal mammary (IM) catheter, all of which have a distal J curve to engage the upgoing vessel (Figs. 56.7 and 56.8). Also, ipsilateral catheterization with these catheters may be difficult to perform with the distal curve so a contralateral access may be needed. Alternatively, a J-curved microcatheter through a non–J-curved main catheter can also be used.

In addition to evaluating the uterine arteries, aortography at the level of the ovarian arteries should be performed if there is any concern for ovarian supply.

Tips

• Always use a microcatheter coaxial to the diagnostic catheter to prevent spasm.

• Ensure that there is pulsatility in the uterine artery during embolization; otherwise, there is spasm which may lead to nontarget embolization.

• The internal iliac artery comes off posteriorly, whereas the anterior division of the internal iliac and uterine arteries come off anteriorly.

• Once the internal iliac is selected, keep the nose of the catheter parallel to the external iliac and positioned anteriorly to guide the tip into the uterine artery.

• Study the ovarian arteries with a flush aortogram. Include the renal arteries because the ovarian arteries can originate off the renal arteries.

• Parasitized collaterals from a malignancy may involve visceral vessels so perform an adequate diagnostic study.

• Look for neovascularity because active bleeding will probably not be seen.

Tricks

• Use Tevdek maneuver to reshape your reversed curve catheter such as the RUC.

• Use BNK or RIM catheter for contralateral catheterization of an upgoing uterine artery.

• Use a curved microcatheter for ipsilateral upgoing uterine arteries because making a reverse curve with a BNK or RIM is difficult.

• Use dry embolic such as PVA with 100% contrast when there is difficulty imaging patients due to large body habitus.

• Use 1-mL polycarbonate syringes to infuse embolic via a three-way stopcock to prevent catheter clogging. One-mL syringe develops higher infusion pressures.

• Use five cardiac beat rule for PVA. No forward progression of contrast within the horizontal segment of the uterine for five beats for general embolization of the uterine artery. Can use the same end point for trisacryl gelatin microsphere but prune tree embolization is adequate.

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