Management of Gestational Trophoblastic Disease

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Management of Gestational Trophoblastic Disease

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Michael J. Seckl and Edward S. Newlands

MAJOR CONTROVERSIES ●

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Are false-positive human chorionic gonadotrophin results a problem, and how should physicians deal with this issue? How should persistently raised low-level human chorionic gonadotrophin of unknown origin be managed? Should twin pregnancies be terminated early? Are registration, centralized follow-up, and therapy after uterine evacuation valuable? Treating low-risk patients: methotrexate or actinomycin D? Treating high-risk patients: EMA/CO regimen or other multiagent treatments? When should therapy be discontinued? Is there a role for high-dose chemotherapy? Does radiotherapy have a role in the management of overt central nervous system disease? What is optimal therapy for placental-site trophoblastic tumors? Is there a role for a nurse specialist?

The first record of gestational trophoblastic disease (GTD) probably dates to about 400 BC, when Hippocrates and his student, Diocles, described “dropsy of the uterus.”1 In 1276, the attendants of Margaret Countess of Henneberg noticed that her abnormal delivery consisted of multiple hydropic vesicles. They probably believed that each vesicle was a separate conception, which led them to christen one half John and one half Mary. Marie Boivin (1773-1841), who worked as a Parisian midwife, was the first to document the chorionic origin of the hydatids.1 In 1895, Marchand described a malignant uterine disease of syncytial and cytotrophoblastic origin and made the link between hydatidiform mole and other forms of pregnancy.1 However, it was not until the mid-20th century that effective therapeutic protocols were developed, which serve as one of the modern success stories in cancer medicine. The normal gestational trophoblast arises from the peripheral cells of the blastocyst in the first few days

after conception. Trophoblastic tissue initially grows rapidly into two layers: an inner cytotrophoblast of mononucleated cells that migrate out and fuse together forming an outer syncytiotrophoblast of large, multi nucleated cells (Fig. 44-1). The latter subsequently aggressively invades the endometrium and uterine vasculature, generating an intimate connection between the fetus and the mother known as the placenta. Invasion is one of the features of malignancy, and normal trophoblastic cells can be detected by polymerase chain reaction in the maternal circulation.2 Fortunately, the complex biologic and immunologic mechanisms involved in controlling the relationship between the fetal trophoblast and the maternal host prevent such circulating trophoblasts from producing metastases. When GTD arises, the normal regulatory mechanisms controlling trophoblastic tissue are lost. The excessively proliferating trophoblast may invade through the myometrium, developing a rich maternal blood supply, with tumor emboli and hematogenous 555

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Gynecologic Cancer: Controversies in Management be preserved. In this chapter, we discuss the current controversies about and management of GTD.

Trophoblastic layer

Pathology and Genetics

Blastocyst

Syncytiotrophoblast

Cytotrophoblast hCG production

Figure 44–1. The schematic diagram of an embryo at the blastocyst stage demonstrates trophoblast development. hCG, human chorionic gonadotrophin.

spread occurring frequently. The World Health Organization (WHO) has classified GTD as two premalignant diseases called complete and partial hydatidiform mole (CM and PM) and as three malignant disorders (i.e., gestational trophoblastic tumors [GTTs]) called invasive mole, gestational choriocarcinoma, and placental-site trophoblastic tumor.3 These tumors are important to recognize because they are nearly always curable, and in most cases, fertility can

Complete hydatidiform mole. CMs nearly always only

contain paternal DNA and are therefore androgenetic.4 This occurs in most cases because a single sperm bearing a 23X set of chromosomes fertilizes an ovum lacking maternal genes and then duplicates to form the homozygote, 46XX (Fig 44-2A).4-9 However, in up to 25% of CMs, fertilization can take place with two spermatozoa, resulting in the heterozygous 46XY or 46XX configuration (see Fig. 44-2B).10,11 A 46YY conceptus has not yet been described and is presumably nonviable. Rarely, a CM can arise from a fertilized ovum that has retained its maternal nuclear DNA and is therefore biparental in origin.12 Macroscopically, the classic CM resembles a bunch of grapes because of generalized (complete) swelling of chorionic villi. However, this appearance is seen only in the second trimester, and the diagnosis is usually made earlier, when the villi are much less hydropic. In the first trimester, the villi microscopically contain little fluid, are branching, and consist of a hyperplastic syncytiotrophoblast and cytotrophoblast with many

Figure 44–2. The schematic

Sperm

diagram shows that the androgenetic diploid complete hydatidiform mole (HM) is formed by duplication of the chromosomes from a single sperm (A) or by two sperm fertilizing the ovum (B), which in both cases has lost its own genetic component. The triploid genetic origin of a partial HM is demonstrated (C).

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Proliferation of monospermic androgenetic complete HM

Proliferation of dispermic androgenetic complete HM

Proliferation of triploid partial HM

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M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 557 vessels. Although it was previously thought that CM produced no fetal tissue, histologic examination of 6- to 8-week abortions reveals evidence of embryonic elements, including fetal red blood cells.13-15 This has resulted in pathologists incorrectly labeling CMs as PMs. Consequently, the reported rates of persistent GTD after PMs has been artificially elevated and is probably less than 0.5%.16 The presence of embryonic tissue from a twin pregnancy comprising a fetus and a CM is another source of error that can lead to the incorrect diagnosis of PM. Occasionally, it can be very difficult to distinguish an early complete mole from a normal early placenta, and in such cases, the absence of p57kip2 staining in the CM as opposed to other types of pregnancy can be helpful.17 Partial hydatidiform mole. PMs are genetically probably all triploid,18 with two paternal and one maternal chromosome sets (see Fig 44-2C). Although triploidy occurs in 1% to 3% of all recognized conceptions and in about 20% of spontaneous abortions with abnormal karyotype, triploids due to two sets of maternal chromosome do not become PMs.19,20 Flow cytometry, which can be done in formalin-fixed, paraffinembedded tissues,21 can therefore help in differentiating CM from PM and PM from diploid nonmolar hydropic abortions. In PMs, villous swelling is less intense and affects only some villi. Swollen and non-swollen villi can have trophoblastic hyperplasia that is mild and focal. The villi have characteristic indented outlines and round inclusions. An embryo is usually present and can be recognized macroscopically or inferred from the presence of nucleated red cells in villous vasculature. It may survive into the second trimester, but in most cases, it dies at about 8 to 9 weeks’ gestation, and this is followed by loss of vessels and stromal fibrosis. In PMs evacuated early, villous swelling and trophoblastic excess can be so mild and focal that the diagnosis of PM may be missed.16 At uterine evacuation for a “miscarriage,” it is likely that many PMs are misclassified as products of conception. Fortunately, at the Trophoblastic Screening and Treatment Center at Charing Cross Hospital, London, we only see about one patient per year with persistent GTD related to a previously unrecognized PM. Of the correctly diagnosed PMs, very few patients go on to develop persistent GTD. Of 3000 PMs reviewed and followed at Charing Cross, only 15 (0.5%) patients required chemotherapy.21 Other pregnancies mistaken for partial hydatidiform mole. More than one half of first-trimester nonmolar

abortions are caused by trisomy, monosomy, maternally derived triploidy, and translocations. They often develop hydrops, but it is small (<3 mm), and PMs can be excluded if the fetuses are diploid on flow cytometry. Turner’s, Edward’s, and Beckwith-Wiedemann syndromes can cause histologic confusion with PMs.16,22 Invasive hydatidiform mole. Invasive mole is common

and is clinically identified by the combination of an abnormal uterine ultrasound scan and a persistent or

rising human chorionic gonadotrophin (hCG) level after uterine evacuation of a CM or PM. Further pathologic confirmation of invasion is rarely required. Moreover, repeat dilatation and curettage (D&C) is often contraindicated because of the risks of uterine perforation, infection, life-threatening hemorrhage, and subsequent hysterectomy. In some cases for which histologic information is available, invasive mole can be distinguished from choriocarcinoma by the presence of chorionic villi. Choriocarcinoma. Most choriocarcinomas have grossly abnormal karyotypes, with diverse ploidies and several chromosome rearrangements, none of which is specific for the disease.23 Studies of the origin of GTTs have confirmed that choriocarcinoma may arise from any type of pregnancy, including a normal term pregnancy24-27 and from a homozygous or heterozygous CM.27,28 Until recently, it was thought that PMs could not give rise to choriocarcinoma. However, there is now incontrovertible genetic evidence proving that PMs can transform into choriocarcinomas.21 This is important because it is wrongly believed by physicians at some centers that it is safe to discontinue hCG follow-up after a diagnosis of PM. Choriocarcinoma is highly malignant and appears as a soft purple, largely hemorrhagic mass. Microscopically, it mimics an early implanting blastocyst with central cores of mononuclear cytotrophoblast surrounded by a rim of multinucleated syncytiotrophoblast and a distinct absence of chorionic villi. There are extensive areas of necrosis and hemorrhage and frequent evidence of tumor within venous sinuses. The disease fails to stimulate the connective tissue support normally associated with tumors and induces hypervascularity of the surrounding maternal tissues. This probably accounts for its highly metastatic and hemorrhagic behavior. Placental-site trophoblastic tumors. Placental-site

trophoblastic tumors (PSTTs) have been shown to follow term delivery, nonmolar abortion, and CM. It is conceivable, although unproven, that PSTT may develop after a PM. Like choriocarcinoma, the causative pregnancy may not be the immediate antecedent pregnancy.29 Genetic analysis of some PSTTs has demonstrated that they are mostly diploid, originating from a normal conceptus and therefore biparental or androgenetic from a CM.30 In the normal placenta, placental-site trophoblast is distinct from villous trophoblast and infiltrates the decidua, myometrium, and spiral arteries of the uterine wall. PSTTs are rare, slow-growing, malignant tumors composed mainly of intermediate trophoblast derived from cytotrophoblast, and they therefore produce little hCG. However, they often stain strongly for human placental lactogen (hPL) and β1-glycoprotein. Elevated Ki-67 levels may help in distinguishing PSTT from a regressing placental nodule.31 In contrast to other forms of GTT, spread tends to occur late by local infiltration and through the lymphatics, although

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Gynecologic Cancer: Controversies in Management

distant metastases can occur. Although some investigators observed a correlation between mitotic index and the subsequent clinical behavior or outcome,30,32 a larger single series failed to confirm this association.33 The role of imprinting. All autosomal genes consist of

two alleles (paternal and maternal). However, some alleles are expressed only from one parent and not the other, a phenomenon called genomic imprinting. Three closely related genes that are imprinted may be involved in GTT development and in other overgrowth syndromes. These are H19, a putative tumor suppressor gene,34 CDKN1C (also designated P57 and KIP2), a cyclin-dependent kinase inhibitor,35 which are normally expressed by the maternal allele, and the paternally expressed IGF2, a growth factor commonly implicated in tumor proliferation.36 Although CDKN1C showed the expected pattern of expression in CM and choriocarcinoma,37 CM and postmole tumors were unexpectedly found to express H19,38 and some postterm tumors showed biallelic expression of H19 and IGF2.39 This suggests that loss of the normal imprinting patterns of these genes may be an important factor in the development of GTT. The identification of rare families in which several sisters have repeat CMs that are biparental in origin12 is likely to shed further light on the genes involved in CM formation. Linkage and homozygosity analysis suggested that in two families there is a defective gene located on chromosome 19q13.3-13.4, where at least one imprinted gene is located.40 However, analysis of another rare family with individuals who have had repetitive biparental CMs has raised the possibility that the genes involved in this disorder may reside on another chromosome.41 This work has also provided data to support the hypothesis that CMs are a consequence of a global disorder in imprinting in the female germline. The identification of the genes underlying GTD is a major goal for the coming years. The results will, for example, enable in vitro testing of early embryos before implantation in women with repetitive molar pregnancies. Human Chorionic Gonadotrophin Assays for β-human chorionic gonadotrophin. The family of pituitary and placental glycoprotein hormones includes hCG, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid stimulating hormone (TSH). Each hormone comprises an α-subunit that is common between the family members and a distinct β-subunit. Consequently, assays to measure hCG are directed against the β-subunit. Many β-hCG assays are available. Some detect intact β−hCG, and others are selective for individual fragments or detect various combinations of hCG fragments or hyperglycosylated forms.42-44 The mechanism of detection is also variable and includes enzyme-linked sandwich assays and radioimmunoassay (RIA). As a result of these differences, great care is required in the

interpretation of results obtained. Pregnancy tests employing hemagglutination inhibition or complement fixation methods have a lower limit of sensitivity of only 2000 IU/L and may give false-negative results when values for hCG are very high. In contrast, some assays, including the modern monoclonal or polyclonal sandwich platforms, can give false-positive readings.45 Are false-positive human chorionic gonadotrophin results a problem, and how should physicians deal with this issue? Although falsely elevated serum hCG

results are rare, they have led clinicians to perform unnecessary medical interventions, including hysterectomy and chemotherapy.46 The consequences can be disastrous, ranging from infertility to induction of second tumors and even death. Not surprisingly, women who have been subjected to this type of unnecessary treatment have sued their doctors and the companies responsible for the hCG assays used. Features that should make the clinician consider an hCG result as potentially false positive include a well patient, absence of a pregnancy or obvious tumor on imaging, and an hCG concentration that does not significantly rise with time. These false-positive results often arise from human anti-mouse antibodies (hAMAs) crossreacting with the mouse monoclonal antibodies used to detect hCG. Because hAMAs do not pass into the urine, a simple test for hCG in the urine using the same assay that is used for serum eliminates this cause of false-positive result. An alternative would be to test the serum with a different type of hCG assay, although it is technically possible for hAMAs to interfere in more than one type of serum assay. The competitive RIA using a polyclonal antibody recognizing all forms of β-hCG remains a gold-standard assay for use in the management of GTD. They are sensitive to 1 IU/L in serum and 20 IU/L in urine and are not generally prone to false-positive readings from heterophilic antibodies such as hAMAs. This is partly because the assays are set up with serial dilutions in which the values for real hCG reduce appropriately but do not in the presence of heterophilic antibodies. However, the competitive RIA is time consuming, requires careful training, and is only as good as the antibodies used. There is general recognition that new assays need to be developed. As we learn more about the various fragments of β-hCG, it may become apparent that certain fragments may be more sensitive for detection of small-volume disease or correlate with poor- or good-prognosis groups.42 Some work suggests that a hyperglycosylated form of β-hCG may be produced only by GTT, rather than by normal trophoblast.43 If this work is confirmed in larger studies, it could provide a major new tool to distinguish between malignancy and a normal pregnancy. Use of human chorionic gonadotrophin as a tumor marker. With a half-life of 24 to 36 hours, hCG is the

most sensitive and specific marker for trophoblastic tissue. However, hCG production is not confined to pregnancy and GTD. The hCG is produced by any trophoblastic tissue found, for example, in germ cell

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 559 tumors and in up to 15% of epithelial malignancies.47 The hCG levels in such cases can be just as high as those seen in GTD or in pregnancy. Current methods for hCG measurement do not reliably discriminate among pregnancy, GTD, and nongestational trophoblastic tumors. However, serial measurements of hCG have revolutionized the management of GTD for several reasons. The amount of hCG produced correlates with tumor volume so that a serum hCG of 5 IU/L corresponds to approximately 104 to 105 viable tumor cells. Consequently, these assays are several orders of magnitude more sensitive than the best imaging modalities available today. The hCG levels can be used to determine prognosis.48,49 Serial measurements allow progress of the disease or response to therapy to be monitored (Fig. 44-3). Development of drug resistance can be detected at an early stage, which facilitates appropriate management changes. Estimates may be made of the time for which chemotherapy should be continued after hCG levels are undetectable in serum to reduce the tumor volume to zero. For these reasons, hCG is the best tumor marker known. How should persistently raised low-level human chorionic gonadotrophin of unknown origin be managed? A small subgroup of the population has a

persistently raised hCG that is detected by chance on investigation for another disorder or as part of a routine health check. Subsequent intensive workup, including exclusion of pituitary disease, fails to show any abnormality apart from the persistently raised hCG that is proved to be genuine and not a false-positive result. There is debate about how best to manage such individuals. Some have advocated a trial of

Mole evacuated

Start treatment

Stop treatment

1000000 MTX MTX MTX MTX MTX MTX

Serum hCG (i.u./l)

100000 10000 1000 100 10 1 0

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Figure 44–3. The graph demonstrates the use of monitoring serum human chorionic gonadotrophin (hCG) concentrations after evacuation of a hydatidiform mole (HM). In this case, after an initial fall, the hCG level started to rise, indicating the development of an invasive HM or choriocarcinoma, and the patient was called in for disease staging. The prognostic score indicated a low risk (see Tables 44-4 and 44-5), and the patient was successfully treated with methotrexate (MTX) and folinic acid (see Table 44-6).

chemotherapy or a hysterectomy, or both, on the assumption that there must be some hCG-secreting tumor cells present that could include an occult PSTT. However, others have suggested careful surveillance with serial hCG monitoring and repeat investigations that should be intensified if the hCG starts to rise.50 Although the latter approach is sensible, in women who have completed their families, hysterectomy may be considered to exclude a PSTT, particularly if the hCG level is rising. At Charing Cross, we had one patient with a slowly rising hCG who was found to have a PSTT even though the D&C, hysteroscopy, laparoscopy, transvaginal Doppler ultrasound, gadolinium-enhanced magnetic resonance imaging (MRI) scan of pelvis and brain, computed tomography (CT) of the body, and [18F]fluoro-2-deoxy-D-glucose– enhanced positron emission tomography (FDG-PET) were negative. Clinical Features Complete and partial moles. CMs and PMs most

commonly manifest in the first trimester as a threatened abortion with vaginal bleeding. If the diagnosis is delayed, patients may notice the passing of grapelike structures (i.e., vesicles), and the entire mole occasionally may be spontaneously evacuated. The uterus may be any size but is commonly large for gestational age. Patients with marked trophoblastic growth and high hCG levels are particularly prone to hyperemesis, toxemia, and the development of theca lutein cysts that may sometimes be palpable above the pelvis. Toxemia was diagnosed in 27% of patients with CMs51 but is seen less frequently today because of early ultrasound diagnosis.52,53 Convulsions rarely occur. The high hCG levels may also produce hyperthyroidism because of crossreactivity between hCG and TSH at the TSH receptor. Although pulmonary, vaginal, and cervical metastases can occur, they may spontaneously disappear after removal of the mole. The presence of metastases does not necessarily imply that invasive mole or choriocarcinoma has developed. Patients rarely present with acute respiratory distress because of pulmonary metastases or anemia and occasionally because of tumor embolization. The risk of embolization is reduced by avoiding agents that induce uterine contraction before the cervix has been dilated to enable evacuation of the CM. Patients with PMs usually do not exhibit the dramatic clinical features characteristic of CMs.54 The uterus is often not enlarged for gestational age, and because vaginal bleeding tends to occur later, patients most often present in the late first trimester or early second trimester with a missed or incomplete abortion. The diagnosis is often only suspected when the histology of curettings is available. The pre-evacuation hCG level is less than 100,000 IU/L at diagnosis in more than 90% of cases. Twin pregnancies. Twin pregnancies comprising a normal fetus and a hydatidiform mole are estimated to occur in 1 of 20,000 to 100,000 pregnancies.55 Some

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probably abort in the first trimester and therefore are undiagnosed. However, some are discovered on ultrasound examination routinely or because of complications such as bleeding, excessive uterine size, or problems related to a high hCG level. Invasive moles. Invasive moles are usually diagnosed

because serial urine or serum hCG measurements reveal a plateaued or rising hCG level in the weeks after molar evacuation. Patients may complain of persistent vaginal bleeding or lower abdominal pains and swelling. This may occur as a result of hemorrhage from leaking tumor-induced vasculature as the trophoblast invades through the myometrium or because of vulval, vaginal, or intra-abdominal metastases. The tumor may involve other pelvic structures, including the bladder or rectum, producing hematuria or rectal bleeding, respectively. Enlarging pulmonary metastases or tumor emboli growing in the pulmonary arteries can contribute to life-threatening respiratory complications.56 The risk of these complications is clearly higher in patients when the initial diagnosis of a molar pregnancy was missed and who therefore are not on hCG follow-up. Choriocarcinoma. Choriocarcinoma can manifest after

any form of pregnancy, but it most commonly occurs after a CM. Histologic proof of choriocarcinoma is usually not obtained after a CM because of the risk of fatal hemorrhage, and it is therefore impossible to distinguish it from invasive mole. Choriocarcinoma after a normal pregnancy or nonmolar abortion usually manifests within a year of delivery but can occur up to 17 years later.57 The presenting features may be similar to hydatidiform mole with vaginal bleeding, abdominal pain, and a pelvic mass. However, one third of all choriocarcinomas manifest without gynecologic features; patients instead suffer from symptoms associated with their distant metastases. In these cases, lives can be saved by remembering to include choriocarcinoma in the differential diagnosis of metastatic malignancy (particularly in lungs, brain, or liver) manifesting in a woman of childbearing age. Any site may be involved, including skin producing a purple lesion, cauda equina, and the heart. Pulmonary disease may be parenchymal or pleural, or it may result form tumor embolism and subsequent growth in the pulmonary arteries.58 Respiratory symptoms and signs can include dyspnea, hemoptysis, and pulmonary artery hypertension. Cerebral metastases may produce focal neurologic signs, convulsions, evidence of raised intracranial pressure, and intracerebral or subarachnoid hemorrhage. Hepatic metastases may cause local pain or referred pain in the right shoulder. Although none of these presentations is specific to choriocarcinoma, performing a simple pregnancy test or quantitative hCG assay can provide a vital clue to the diagnosis. Infantile choriocarcinoma. Choriocarcinoma in the

fetus or newborn is rare, with approximately 26 cases reported.59 Although a primary choriocarcinoma

within the infant is possible, in 11 cases, the mother also had the tumor. The diagnosis was often made in the neonate before the mother. In all cases, the infant was anemic and had a raised hCG level, but the site of metastasis was varied, including brain, liver, lung, and skin. Only six cases have been successfully treated; the rest died within weeks of the initial diagnosis, which might have been delayed. Consequently, serum or urine hCG levels should be measured in all babies of mothers with choriocarcinoma. Because the disease can manifest up to 6 months after delivery, an argument can be made for serial monitoring of hCG levels in these infants. Placental-site trophoblastic tumor. A PSTT grows slowly and can manifest years after a term delivery, nonmolar abortion, or CM. Unlike choriocarcinoma, it tends to metastasize late in its natural history, and patients frequently present with gynecologic symptoms alone. In addition to vaginal bleeding, the production of hPL by the cytotrophoblastic cells may cause hyperprolactinemia that can result in amenorrhea or galactorrhea, or both. Rarely, patients can develop nephrotic syndrome or hematuria and disseminated intravascular coagulation. Metastases may occur in the vagina, extrauterine pelvic tissues, retroperitoneum, lymph nodes, lungs, and brain. The serum hCG levels can be higher than 50,000 IU/L but are usually low, measuring less than 500 IU/L in 58% of patients in one series.30,33

Investigations Human chorionic gonadotrophin, plain chest radiographs, and pelvic Doppler ultrasonography. All

patients who are suspected of having GTTs should have serum and urine hCG level tests, a chest radiograph, and pelvic Doppler ultrasound. The most common metastatic appearance on a chest radiograph is multiple, discrete, rounded lesions, but large and solitary lesions, a miliary pattern, and pleural effusions can occur.60 Tumor emboli to the pulmonary arteries can produce an identical picture to venous thromboembolism with wedge-shaped infarcts and areas of decreased vascular markings. Pulmonary artery hypertension can cause dilatation of the pulmonary arteries. Routine CT scanning of the chest does not add anything to the management of these cases.61 Ultrasound and color Doppler imaging is not diagnostic but is highly suggestive of molar disease52,53 or persistent GTD62 when there is a combination of a raised hCG level, no pregnancy, and a vascular mass within the uterus (Fig. 44-4). The latter is seen in more than 75% of patients with persistent trophoblastic disease after initial evacuation of the uterus. The determination of uterine volume correlates with the amount of disease, and uterine volume and the degree of abnormal tumor vasculature independently predict the likelihood of resistance to single-agent methotrexate therapy.49 The vascular abnormalities within the pelvis and uterus can persist long after the disease has been

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 561 PET has been reported to distinguish GTT emboli from blood clot in two patients with choriocarcinoma.65 PET with various compounds, such as FDG, which can identify tumors missed by other techniques,66 has yet to prove an aid in the location of drug-resistant GTTs. Genetic analysis. On some occasions, it can be helpful

to perform a comparative genetic analysis of the patient’s trophoblastic tumor with her normal tissue and, if available, with that of her partner. If the tumor is suspected to be of nongestational origin, this status can be confirmed by the presence of only maternal DNA and the complete absence of paternal DNA. Genetic studies can also determine which of several antecedent pregnancies is the causal pregnancy of the current GTT. This can have an impact on determining appropriate therapy and prognosis.12 Figure 44–4. Ultrasonography with color Doppler shows persistent gestational trophoblastic disease after removal of a complete hydatidiform mole within the body and wall of the uterus. A typical vesicular or “‘snowstorm” appearance of residual molar tissue can be seen within the uterus together with a rich blood supply throughout the endometrium and myometrium. There is no evidence of a fetus. See also Color Figure 44-4.

eradicated with chemotherapy. This is usually of no consequence. However, some patients suffer repeated vaginal hemorrhages from these vascular malformations and require selective arterial embolization. This may need to be repeated on several occasions but is usually successful and does not appear to affect fertility.63 A pelvic ultrasound scan can also demonstrate ovarian theca lutein cysts and other ovarian masses. Metastatic spread outside the pelvis, such as to the liver or kidneys, can be identified and shown to have an abnormal Doppler signal. Investigation of drug-resistant disease. When patients develop drug-resistant disease, further investigation is required to more accurately define where the residual tumor is located because resection can be curative. CT of the chest and abdomen together with MRI of the brain and pelvis is often helpful and can detect deposits not previously seen. If the CT and MRI scans are normal, a lumbar puncture to measure the hCG level in cerebrospinal fluid (CSF) can be useful to detect disease in the central nervous system. An hCG ratio greater than 1:60 (CSF to serum) of that found in the serum is highly indicative of the presence of trophoblastic disease. Experimental imaging techniques. Radiolabeled anti-hCG antibodies given intravenously can localize tumors producing hCG when the serum hCG level is higher than 100 IU/L.64 Because false-positive and false-negative results occur, anti-hCG scanning should be regarded as complementary to other imaging investigations. PET has provided a novel way to image many types of tumors using a variety of labels. Whole-body

Management Molar evacuation. Evacuation of the uterine cavity using suction gives the lowest incidence of sequelae.67,68 When the molar trophoblast invades the myometrium, it is relatively easy to perforate the uterus if a metal curette is used. Medical induction involving repeated contraction of the uterus induced by oxytocin or prostaglandin or other surgical approaches, including hysterectomy and hysterotomy, increases the risk of requiring chemotherapy by twofold to threefold compared with suction evacuation. This is thought to occur because tumor is more likely to be disseminated by uterine contraction and manipulation. For similar reasons, the use of prostanoids to ripen a nulliparous cervix is not recommended even in nulliparous women.68 If bleeding is severe immediately after suction evacuation, a single dose of ergometrine to produce one uterine contraction may stem the hemorrhage and does not appear to increase the chance of requiring chemotherapy. In the past, it has been common practice for gynecologists to perform a second and sometimes a third evacuation of the uterine cavity in patients with a molar pregnancy. However, the chances of requiring chemotherapy after one evacuation is only 2.4% but rises markedly to 18% after two evacuations and to 81% after four evacuations (Table 44-1). Consequently, a second evacuation may be reasonable and should be discussed with the local GTD center if there is vaginal bleeding in the presence of persisting molar trophoblast within the uterine cavity. The use of ultrasound control during this procedure may help to reduce the risk of uterine perforation. Further evacuations are not recommended because of the risk of complications and the high likelihood that the patient will require chemotherapy anyway. Should twin pregnancies be terminated early? At

Charing Cross Hospital in London, we have seen 77 confirmed cases of CM with a separate normal conceptus. The management of twin pregnancies

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Gynecologic Cancer: Controversies in Management

Table 44–1. Correlation between the Number of Evacuations Performed for a Hydatidiform Mole and the Subsequent Requirement for Chemotherapy at Charing Cross Hospital, 1973-1986 No. of Evacuations 1 2 3 4

Patients Not Treated

Patients Treated

Patients Treated (%)

4481 1495 106 5

109 267 106 22

2.4 18 50 81

comprising a normal fetus and a CM is difficult because they can be associated with complications such as fetal death, severe vaginal bleeding, preeclampsia, and a possible increased risk of persistent GTD requiring chemotherapy.69-71 In our series, although 24 women elected to have an early termination, 53 decided to continue their pregnancies. Nearly 40% of these resulted in live births, most of which occurred beyond 32 weeks’ gestation. The remaining women mostly spontaneously terminated their pregnancies before 24 weeks. The risk of severe preeclampsia was 6%. Strikingly, women continuing their pregnancies did not have a significantly increased risk of persistent GTD requiring chemotherapy. Moreover, there were no maternal deaths. It appears reasonably safe to allow patients with twin pregnancies in which one of the conceptions is a CM to continue to term, provided there are no other complications.55 Are registration, centralized follow-up, and therapy after uterine evacuation valuable? Most patients

require no more treatment after evacuation, but 16% of patients with CM and less than 0.5% with PM develop persistent GTD. It is vital that patients with persistent GTD be rapidly identified because virtually all of them can be cured with appropriate therapy. In 1973, under the auspices of the Royal College of Obstetricians and Gynecologists, a national follow-up service was instituted in the United Kingdom whereby patients with GTD are registered with one of three laboratories located in Dundee, Sheffield, and London. Approximately 1400 women are registered per annum, and 110 to 120 require subsequent chemotherapy, with 85 being treated in the London center and the rest in Sheffield. After registration, the patient’s details and pathology together with two weekly blood and urine samples are sent through the mail to one of the reference laboratories for confirmation of diagnosis and serial hCG estimations. This scheme has been very successful and has enabled refinement of treatments that would otherwise not have been possible. Similar centralized registration and treatment has been established in the Netherlands72 and Korea73 but has not yet been achieved in the United States or in other European countries. The failure to centralize the registration and subsequent management of GTD patients in these countries has resulted in patchy standards of care. Moreover, despite guidelines, these recommendations can never be detailed enough to substitute for

Table 44–2. Factors Increasing the Requirement of Chemotherapy after Evacuation of a Hydatidiform Mole Factor

Study

Uterine size > gestational age Pre-evacuation serum human chorionic gonadotropin (hCG) level > 100,000 IU/L Oral contraceptives given before hCG falls to normal Bilateral cystic ovarian enlargement

Curry et al.138 (1975) Berkowitz and Goldstein51 (1981) Stone et al.74 (1976) Zongfu et al.139 (1979); Berkowitz and Goldstein51 (1981)

the experience gained in treating thousands rather than tens of patients. In most cases, the molar tissue dies spontaneously, the hCG concentration returns to normal (about 4 IU/L), and the patient can start a new pregnancy after another 6 months. If the hCG level has fallen to normal within 8 weeks of evacuation, marker follow-up can be safely reduced to 6 months because none of these patients has required chemotherapy. However, in patients whose hCG levels are still elevated beyond 8 weeks from the date of evacuation, follow-up should continue for 2 years. Because patients who have had a previous mole or GTT are more at risk of having a second, all patients should have a further estimation of hCG at 6 and 10 weeks after the completion of each subsequent pregnancy. Indications for chemotherapy. Factors associated with an increased risk of requiring chemotherapy are summarized in Table 44-2. The hormones in the oral contraceptive pill (OCP) are probably growth factors for trophoblastic tumors, and for this reason, patients are advised not to use the pill until the hCG levels have returned to normal.74,75 Prior duration of OCP use may also increase the risk of developing a molar pregnancy.76 The indications for intervention with chemotherapy in patients who have had a CM or PM are shown in Table 44-3. The hCG value of 20,000 IU/L 4 weeks after evacuation of a mole or rising values in this range at an earlier stage indicate the patient is at increased

Table 44–3.

Indications for Chemotherapy

Any of the following conditions are indications to treat after a diagnosis of gestational trophoblastic disease: 1. Evidence of metastases in the brain, liver, or gastrointestinal tract or radiologic opacities > 2 cm on chest radiograph 2. Histologic evidence of choriocarcinoma 3. Heavy vaginal bleeding or evidence of gastrointestinal or intraperitoneal hemorrhage 4. Pulmonary, vulval, or vaginal metastases unless the human chorionic gonadotropin (hCG) level is falling 5. Rising hCG level after evacuation 6. Serum hCG ≥ 20,000 IU/L more than 4 weeks after evacuation, because of the risk of uterine perforation 7. Raised hCG level 6 months after evacuation, even if the level is still falling

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 563 Table 44–4.

Scoring System for Gestational Trophoblastic Tumors Score*

Prognostic Factor

0

1

2

6

Age (years) Antecedent pregnancy (AP) Interval: end of AP to chemotherapy at CXH† (months) Human chorionic gonadotropin (IU/L) ABO blood group (female × male)

<39 Mole <4

>39 Abortion or unknown 4-7

Term 7-12

>12

103-104

No. of metastases Site of metastases

None Not detected, lungs, vagina

<103 A×O O×A O or A × unknown 1-4 Spleen, kidney

Largest tumor mass Prior chemotherapy

3-5 cm

104-105 B × A or O AB × A or O

>105

4-8 Gastrointestinal tract

>8 Brain, liver

>5 cm Single drug

Two or more drugs

*The total score for a patient is obtained by adding the individual scores for each prognostic factor: low risk, 0-5; medium risk, 6-8; high risk, ≥9. Patients scoring 0-8 receive single agent therapy with methotrexate and folinic acid, and patients scoring ≥9 receive combination drug therapy with a regimen consisting of etoposide, methotrexate, and actinomycin D (EMA) alternating weekly with cyclophosphamide and vincristine (Oncovin) (CO). † Charing Cross Hospital.

risk of severe hemorrhage or uterine perforation with intraperitoneal bleeding. These complications can be life threatening, and their risk can be reduced by starting chemotherapy. Metastases in the lung, vulva, and vagina can be observed only if the hCG levels are falling. However, if the hCG levels are not dropping or the patient has metastases at another site, which can indicate the development of choriocarcinoma, chemotherapy is required. Prognostic factors and FIGO staging. The principal prognostic variables for GTTs, which were originally identified by Bagshawe48 and since modified by the WHO and our own experience, are summarized in Table 44-4. They have been combined with the FIGO staging system to give the unified staging and scoring system shown in Table 44-5.77 Each variable carries a score that, when added together for an individual patient, correlates with the risk of the tumor’s becoming resistant to single-agent therapy. The most important prognostic variables carry the highest score and include (1) the duration of the disease, because drug resistance of GTTs varies inversely with time from the original antecedent pregnancy; (2) the serum hCG concentration, which correlates with viable tumor volume in the body; and (3) the presence of liver or brain metastases. ABO blood groups (see Table 44-4) contribute little to the overall scoring and therefore have been removed from the current system (see Table 44-5). Types of chemotherapy. At Charing Cross, we have used the prognostic scoring system in Table 44-4 to subdivide the patients into three groups, categorized as low, medium, and high risk depending on their overall scores. Formerly, each risk group corresponded with a separate treatment regimen, and there were three types of treatment called low-, medium-, and high-risk therapy. Several years ago, we discontinued

the medium-risk treatment for three reasons. First, the short- and long-term toxicity of this treatment is probably not significantly different from high-risk therapy. Second, some patients treated with mediumrisk therapy have developed drug resistance and subsequently required high-risk therapy. Third, about 30% of medium-risk patients can still be cured on lowrisk chemotherapy, which is less toxic than mediumor high-risk chemotherapy.78 Moreover, there is no evidence that prior treatment failure with methotrexate is an adverse prognostic variable.79,80 Accordingly, patients who score between 0 and 8 (0 to 6 in the unified/FIGO scoring system) receive low-risk chemotherapy. Patients scoring 9 (7 in the unified/FIGO scoring system) are given high-risk treatment. The details of low- and high-risk treatment are discussed later. Patients are admitted for the first 1 to 3 weeks of therapy, principally because the tumors are often highly vascular and may bleed vigorously in this early period of treatment. Treating low-risk patients: methotrexate or actinomycin D? Most centers in the world treat low-

risk patients with single-agent methotrexate plus folinic acid rescue (MTX/FA) or with actinomycin D. A variety of different regimens have been developed for administering these drugs. Many of the reported differences in overall response rates are likely accounted for by differences in total numbers studied, entry criteria, and the decision about when to stop therapy. Methotrexate has been given as an intravenous bolus with or without folinic acid rescue on a daily, weekly, two-weekly, or even less frequent basis.81-84 It has also been given intramuscularly with or without folinic acid.85-87 Oral administration has not been favored because of the variable absorption and bioavailability. In developing countries, omission of folinic acid may be advantageous as a cost-cutting measure.83

564

Gynecologic Cancer: Controversies in Management Table 44–5.

WHO Prognostic Scoring System as Modified by FIGO

Scores

0

Age (years) Antecedent pregnancy Interval (months) from index pregnancy Pretreatment serum human chorionic gonadotropin (IU/ L) level Largest tumor size (including uterus) Site of metastases Number of metastases identified Previous chemotherapy failed

2

4

<40 Mole <4 <103

≥40 Abortion 4-<7 103-<104

— Term 7-<13 104-<105

≥13 ≥105

— Lung — —

3-<5 cm Spleen, kidney 1-4 —

≥5 cm Gastrointestinal 5-8 Single drug

— Brain, liver >8 Two or more drugs

The cure rates with methotrexate are generally more than 60%. Failure to cure is usually caused by the onset of methotrexate resistance or toxicity. Some work has provided further evidence that daily or alternate-daily therapy over 1 week may provide superior antitumor effects and cure rates than weekly or less frequent pulsed administration.88 Biologically, this observation makes sense because GTT is often rapidly growing and infrequent administration of drugs is likely to allow regrowth of tumor between doses. The regimen used since 1964 at Charing Cross Hospital and widely followed in other centers is shown in Table 44-6. This schedule is well tolerated and causes no alopecia, and because the folinic acid dose was increased from 7.5 to 15 mg, the incidence of mucosal ulceration has been dramatically reduced from 20%86 to less than 2%80 (and our unpublished observations). Methotrexate can induce serositis resulting in pleuritic chest pain or abdominal pain. Myelosuppression is rare, but a full blood cell count should be obtained before each course of treatment. Liver and renal function should also be regularly monitored. Transient elevation of the liver function tests can occur, but in our experience, this has not necessitated a change in therapy. In an evaluation of patients treated between 1992 and 2000, two thirds of 485 treated women were cured with MTX/FA alone. One third required a change of therapy, largely because of drug resistance detected by a plateau or rising serum hCG concentration over three or more values (only 2% changed because of toxicity). The remaining women were subsequently cured with single-agent actinomycin D given intravenously at a dose of 0.5 mg daily for 5 days or by multiagent chemotherapy with EMA/CO (described later).80

Table 44–6. Chemotherapy Regimen for Low-Risk and Intermediate-Risk Patients Drug

Schedule*

Methotrexate (MTX)

50 mg by IM injection, repeated every 48 hr × 4 15 mg orally 30 hr after each injection of MTX (folinic acid)

Calcium folinate

1

*Courses are repeated every 2 weeks (i.e., days 1, 15, 29, and so on).

—

Actinomycin D was chosen if the serum hCG level was up to 100 IU/L, and EMA/CO was given when the hCG level was more than 100 IU/L. Over the past 40 years at our institution, one patient receiving MTX/FA died of concurrent and nontherapyinduced lymphoma, and one died of hepatitis.80,86 There have been no therapy-induced second tumors.78 Like methotrexate, several intravenous actinomycin D regimens have been developed, but the available evidence suggests that daily administration over 5 days every 2 weeks is more efficacious and probably as well tolerated as the pulsed once- or twice-weekly regimens.80,86,88-91 The overall efficacy is more than 60% and is probably higher than with MTX/FA, although a formal head-to-head study has not been performed. However, the short-term toxicity of actinomycin D is greater. Unlike methotrexate, actinomycin D can induce transient alopecia, although it is usually mild. Actinomycin D also induces nausea, myelosuppression, and oral ulceration that tend to be worse than with methotrexate. The long-term toxicity of actinomycin D probably does not significantly differ from MTX/FA, but this has yet to be fully reported. In view of the increased short-term toxicity of actinomycin D and the greater ease of community administration of MTX (intramuscularly rather than intravenously), we have continued to favor the MTX/FA regimen as first-line therapy for low-risk GTT patients. Treating high-risk patients: EMA/CO regimen or other multiagent treatments? Some patients are at high

risk for developing drug resistance to single-agent chemotherapy. Since 1979, we have treated them with an intensive regimen consisting of etoposide, methotrexate, and actinomycin D (EMA) alternating weekly with cyclophosphamide and vincristine (Oncovin) (CO) (Table 44-7). The regimen requires one overnight stay every 2 weeks and causes alopecia and myelosuppression, which are reversible. About 70% of patients require granulocyte colony-stimulating factor support during therapy to maintain treatment intensity.79 Other short-term toxicities include mucositis and vincristine-induced neuropathy. The cumulative 5-year survival rate for 272 patients treated with this regimen in our center is 86%, with no deaths from GTT beyond 2 years after the initiation of chemotherapy.79 Although these results are good,

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 565 Table 44–7. Day EMA 1

2

CO 8

Chemotherapy Regimen for High-Risk Patients

Drug

Schedule*

Etoposide Actinomycin D Methotrexate Etoposide Actinomycin D Folinic acid rescue starting 24 hr after commencing the methotrexate infusion

100 mg/m2 by IV infusion over 30 min 0.5 mg by IV bolus 300 mg/m2 by IV infusion over 12 hr 100 mg/m2 by IV infusion over 30 min 0.5 mg by IV bolus 15 mg IM or orally every 12 hr × 4 doses

Vincristine Cyclophosphamide

1 mg/m2 by IV bolus (max. of 2 mg) 600 mg/m2 by IV infusion over 30 min

*A regimen consisting of etoposide, methotrexate, and actinomycin D (EMA) alternates weekly with cyclophosphamide and vincristine (Oncovin) (CO). To avoid extended intervals between courses caused by myelosuppression, it may occasionally be necessary to reduce the EMA by omitting the day 2 doses of etoposide and actinomycin D.

the presence of liver metastases or brain metastases correlated with 30% or 70% long-term survival, respectively. Patients with both liver and brain involvement appear to fare particularly badly, with only one of five surviving in our series.92 A later analysis of patients with brain metastases suggested that the survival might not be so poor, with 86% surviving, if those dying within 8 days of admission are excluded.92 Early deaths accounted for a significant portion of the overall mortality; causes included respiratory failure, cerebral metastases, hepatic failure, and pulmonary embolism. These women did not have preceding moles, were not registered for follow-up, and therefore presented with extensive disease. It will be difficult to improve the survival of this particular subgroup. However, any woman of childbearing age presenting with widespread malignancy should have an hCG measurement, because very high levels of this hormone are highly suggestive of choriocarcinoma. The long-term risk of chemotherapy-induced second tumors in patients treated for GTTs in our center has been reviewed78 and is discussed in “Long-Term Complications of Therapy.” EMA/CO is being used in most centers with similar impressive survival results of between 80% and 90%.93-98 Other regimens that have been used to treat high-risk GTT include combinations of methotrexate, actinomycin D, and etoposide given on a weekly to thrice-weekly basis, combined methotrexate actinomycin D and cyclophosphamide and with hydroxyurea, actinomycin D, methotrexate, folinic acid, cyclophosphamide, vincristine, and doxorubicin (CHAMOCA). Most of these regimens appear in nonrandomized studies to be less effective than EMA/CO,96 and some increase the exposure to etoposide,99,100 which although active is clearly proved to induce second tumors.101 Consequently, we believe that the current optimum therapy for initial treatment of uncomplicated highrisk GTT is EMA/CO therapy. The goal for the future will be to introduce agents that reduce the risk of toxicity such as second tumors without compromising efficacy.

When should therapy be discontinued? After the serum hCG has returned to normal, we estimate that there are still about 105 tumor cells left. Consequently, discontinuing therapy when the hCG level is just normal would likely result in higher relapse rates. For this reason, we have elected to continue therapy for 6 weeks after the hCG level is normal, which translates into three courses of MTX/FA or EMA/CO for lowrisk or uncomplicated high-risk disease, respectively. Patients with complicated high-risk disease with, for example, overt central nervous system (CNS) or liver metastases or who have a score higher than 12 are usually given 8 rather than 6 weeks of continued therapy with a normal hCG level. Using this protocol, the relapse rate is approximately 3%.79,80 It is unclear whether this time could be shortened without compromising outcome. At least one group stops therapy after the hCG level is normal in low-risk patients without increasing their relapse rate (D. Goldstein, personal communication, 2002). However, the criteria for treating patients at this center are more inclusive than at our unit; because more patients are treated than necessarily require therapy, comparison of results with the Charing Cross data set is not straightforward. The use of hCG algorithms identifying rates of fall could be helpful. Patients with rapid decreases may need less chemotherapy after the hCG level is normal. Future trials may randomize low-risk patients with a rapid fall in the hCG concentration to fewer courses of MTX/FA by, for example, stopping after one rather than three cycles when the serum hCG level is normal. Management of drug-resistant disease. Low-risk disease. Frequent measurement of the

serum hCG level is a simple way to detect drug resistance at an early stage because the hormone levels stop falling and may start to rise long before there are other clinical changes. Decisions to alter treatment are not made on the basis of a single hCG result but on a progressive trend over two or three values. In patients receiving MTX/FA for low-risk disease, if the hCG is 100 IU/L when drug resistance occurs, the disease can

566

Gynecologic Cancer: Controversies in Management

often be cured simply by substituting actinomycin D (0.5 mg total dose given intravenously daily for 5 days every 2 weeks). If the hCG is higher than 100 IU/L when developing resistance to MTX/FA, all cases are usually cured with EMA/CO.80 If actinomycin D is used as the initial therapy, similar salvage can be achieved by switching to MTX/FA when resistance occurs at a low serum level of hCG. Patients who are treated with once-weekly or alternate-week pulsed actinomycin D can sometimes be salvaged by increasing the frequency of administration to daily actinomycin D for 5 days every 2 weeks.88 High-risk disease. Most patients who have failed

EMA/CO for high-risk disease can still be salvaged by further chemotherapy or surgery, or both.79 The combination of surgical removal of the main site of drug resistance (usually uterus, lung, or brain) together with chemotherapy is particularly effective. Preoperative investigations include transvaginal or abdominal ultrasound Doppler of the pelvis, possible repeat D&C or hysteroscopy, CT scan of the whole body, MRI of the brain and pelvis, lumbar puncture to measure hCG levels in the CSF, and experimental imaging techniques such as anti-hCG or FDG-PET scanning. If all these investigations are negative, hysterectomy should be considered. When multiple possible sites of resistant disease are found, anti-hCG or FDG-PET imaging can potentially distinguish the biologically active from dead or necrotic lesions and thereby guide appropriate surgery. After surgery or when surgery is not appropriate, we use the cisplatincontaining regimen of EP (150 mg/m2 of etoposide and 75 mg/m2 of cisplatin with hydration) alternating weekly with EMA (omitting day 2, except the folinic acid). Although this regimen is toxic (myelosuppression is common and great care of renal function is required), the outcome has been impressive, with survival rates in excess of 80%.102 Other regimens that have been tried but found to be less effective include platinum, vinblastine, and bleomycin (PVB) and bleomycin, etoposide, and cisplatin (BEP).103-105 Current alternative options include use of some of the new anticancer agents such as the taxanes, topotecan, gemcitabine, irinotecan, and oxaliplatin. Paclitaxel has been shown to have activity in patients with germ cell tumors that have failed on prior treatment.106 Three cases of drug-resistant GTT responded to paclitaxel, with one remaining in remission,107,108 and in another report, a fourth patient remains in remission after high-dose paclitaxel (250 mg/m2 repeated every third week).109

case reports of remissions after high-dose chemotherapy with cyclophosphamide, etoposide, and melphalan112 and chemotherapy with carboplatin, etoposide, and ifosfamide113 or cyclophosphamide.114 At Charing Cross, we have used high-dose carboplatin etoposide and cyclophosphamide in one and added paclitaxel for three other patients failing EMA/CO or EP/EMA, or both. Despite transient responses, none has achieved a durable remission. Consequently, the jury remains out on the value and timing of high-dose therapy for GTT. Management of acute, disease-induced complications. Hemorrhage. Heavy vaginal or intraperitoneal bleed-

ing is the most common immediate threat to life in patients with GTT. The bleeding usually slows down and stops with bed rest and appropriate chemotherapy. However, the bleeding occasionally can be torrential, requiring massive transfusion. In this situation, if the bleeding is coming from the uterus, it may be necessary to consider a vaginal pack or emergency embolization of the tumor vasculature. Fortunately, hysterectomy is rarely required. If the bleeding is intraperitoneal and does not settle with transfusion and chemotherapy, laparotomy may be required. Patients occasionally present this way. Respiratory failure. Occasionally, patients present with respiratory failure caused by multiple pulmonary metastases or rarely as a result of massive tumor embolism to the pulmonary circulation as shown in Figure 44-5.56,58 However, in our experience, these patients can be cured with appropriate management. Pulse oximetry and arterial blood gas determinations should be done regularly to allow appropriate adjustment of oxygen therapy and to monitor any deterioration in pulmonary function that may occur after the start of chemotherapy. The latter occurs probably because of edema and inflammation around tumor deposits that are becoming necrotic. To prevent this, we usually commence therapy with only etoposide (100 mg/m2) and cisplatin (20 mg/m2) given on days 1 and 2, repeated after 1 week, and we introduce the other drugs after pulmonary function is stable. Oxygen support may be required, including masked continuous positive airway pressure ventilation, but mechanical ventilation is contraindicated because it results in trauma to the tumor vasculature, leading to massive intrapulmonary hemorrhage and death. For this reason extracorporeal oxygenation has been proposed.115 Management of cerebral metastases. Involvement of

Is there a role for high-dose chemotherapy? High-

dose chemotherapy with autologous bone marrow or peripheral stem cell transplantation provides another strategy for managing high-risk, EMA/CO-resistant patients. Patient selection is probably important in determining outcome. We know from experience with refractory germ cell tumors that patients with drug-sensitive disease are the ones that stay in remission.110,111 There have been three encouraging

the CNS by GTT may be overt and require intensive therapy or occult and need prophylaxis. Any patient with a GTT who has lung metastases is at risk for CNS disease.116 The second most common site of metastases in high-risk patients is the CNS, and nearly all of these individuals have had lung deposits.116 Neurologic symptoms and signs may alert the clinician to the presence of brain metastases. However, some high-risk patients do not have overt pulmonary or CNS disease

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 567 headaches in up to 40% of patients. We have been able to eliminate the problem of headaches by using epidural-type spinal needles.117 In a series of 67 patients who had lung metastases and received no CNS prophylaxis, one patient who was poorly compliant with therapy subsequently developed CNS disease.118 Does radiotherapy have a role in the management of overt central nervous system disease? Overt CNS

Figure 44–5. Contrast-enhanced computed tomography (CT) of the thorax at the level of the main pulmonary arteries shows a filling defect in the right main pulmonary artery (arrow). The patient presented with a brief history of increasing shortness of breath that had suddenly worsened. During the previous 18 months, she had suffered from irregular, heavy vaginal bleeding; had four separate positive pregnancy tests; and had two pelvic ultrasound investigations with normal results. She was successfully treated with EMA/CO chemotherapy, with some resolution of the changes seen on CT and ventilation-perfusion scanning. Postmortem examinations of similar cases have revealed that the filling defect in the main pulmonary artery is a tumor embolus, not a clot. (From Seckl MJ, Rustin GJS, Newlands ES, et al: Pulmonary embolism, pulmonary hypertension, and choriocarcinoma. Lancet 1991;338:1313-1315.)

at presentation but subsequently develop cerebral metastases that are then drug resistant. Consequently, careful investigation of patients at risk for developing brain metastases is warranted so that appropriate CNS-penetrating chemotherapy is given rather than the standard low- or high-risk treatments. Investigations include contrast-enhanced CT or (preferably) MRI of the brain, and in patients who do not have raised intracranial pressure, the hCG levels in CSF should be measured. A CSF-to-serum ratio of hCG that is greater than 1:60 suggests the presence of CNS disease. Central nervous system prophylaxis. At Charing Cross, prophylaxis against possible CNS disease (i.e., MRI of brain is normal) is given to patients from all risk categories with lung metastases and all high-risk patients, regardless of the absence or presence of lung deposits. The prophylaxis consists of 12.5 mg of methotrexate administered intrathecally, followed 24 hours later by 15 mg of folinic acid given orally. This prophylaxis is given with every course of low-risk therapy or with each CO in the high-risk therapy for three doses. Since the introduction of this policy, the development of brain metastases without evidence of drug resistance elsewhere has been rare.116 Nevertheless, others have not adopted a policy of prophylaxis partly because lumbar punctures are invasive and can induce

disease requires careful management because therapy can induce hemorrhage in the tumor, leading to a rise in intracranial pressure and subsequent loss of life.92,116 We and others have found that early resection of solitary brain deposits in patients with serious neurologic signs can sometimes be lifesaving.119-121 Alternatively, some have argued that emergency radiotherapy can reduce acute bleeding or the subsequent risk of bleeding.122 However, there is no biologic mechanism to explain how radiotherapy can acutely stop bleeding, and we do not recommend this approach. To reduce cerebral edema, patients are given 24 mg of dexamethasone in divided doses before starting chemotherapy. By starting chemotherapy gently with low-dose etoposide and cisplatinum over 2 days (as described earlier for severe pulmonary disease), it is possible to reduce the risk of worsening edema and hemorrhage. Subsequently, the EMA/CO regimen is modified by increasing the dose of methotrexate to 1 g/m2, given as a 24-hour infusion on day 1. The folinic acid rescue is increased to 30 mg, given every 8 hours intravenously for 3 days, commencing 32 hours after the start of the methotrexate infusion. Provided there is no evidence of raised intracranial pressure, 12.5 mg of methotrexate is given intrathecally with each CO dose, with 15 mg of folinic acid rescue 24 hours later, until the serum hCG level is normal. Modified EMA/CO is then continued for another 6 to 8 weeks. Patients who survive the first 8 days of such treatment have a good prognosis, with an 86% chance of cure.92,121 Patients who develop cerebral tumor during chemotherapy have a poor prognosis because their disease is almost certainly drug resistant. Nevertheless, a combination of immediate surgery to remove the deposits and modified chemotherapy designed to provide better CNS penetration can be curative in this situation.92,116,121 Whole-brain radiotherapy alone or in combination with chemotherapy has been advocated as an alternative therapeutic approach in the management of CNS disease.123,124 However, it has not been shown to eradicate tumor in its own right, and in combination with chemotherapy, it has produced less effective results than chemotherapy alone.116,121 Moreover, there is potential for more long-term CNS toxicity when combining whole-brain radiotherapy with chemotherapy. Nevertheless, there is probably a role for using stereotactic radiotherapy after chemotherapy for persistent, isolated, deep lesions that cannot be removed surgically.92 What is optimal therapy for placental-site trophoblastic tumors? PSTTs differ from the other forms of GTD and

produce little hCG, grow slowly, metastasize late, and

568

Gynecologic Cancer: Controversies in Management

are relatively resistant to combination-chemotherapy regimens. Hysterectomy therefore remains the treatment of choice, provided the disease is localized to the uterus. Because the disease usually spreads to local pelvic lymph nodes before distant metastases occur, pelvic lymphadenectomy should be performed. For young women without a family history of ovarian cancer, we recommend conservation of the ovaries. When metastatic disease is present, individual patients can respond and be apparently cured by chemotherapy (EP/EMA) alone or in combination withsurgery.30,32,33,102 Radiotherapy has produced mixed results and has not been proved to cure the disease. The prognostic scoring system cannot be used to determine the treatment of these patients. However, several prognostic variables have been identified, and probably the most important is the interval from the last pregnancy. When this is less than 4 years, the prognosis is good, and when it is more than 4 years, the outcome is almost universally fatal.33,125 Because PSTT is rare, it is unlikely that its treatment will ever be optimized. Patient follow-up after chemotherapy. On completion

of their chemotherapy, patients are monitored regularly with hCG estimations (Table 44-8) to confirm that their disease is in remission. At Charing Cross, we review patients 6 weeks after chemotherapy, repeating any initial staging investigations that were positive. Although in most instances pulmonary metastases or uterine vascular malformations disappear, such abnormalities can persist. These are of no consequence unless the serum hCG level rises, and we therefore do not advocate routine repeat chest radiographs or Doppler ultrasound scans to follow these residual abnormalities. Occasionally, persistent uterine vascular malformations can be associated with serious per vaginum (PV) bleeding and require embolization as shown in Figure 44-6. Such procedures may need to be repeated to achieve control of the problem. Fortunately, fertility does not appear to have been compromised in women who have attempted subsequent pregnancies.63 The risk of GTT relapse is about 3% and is most likely in the first year of follow-up. We continue hCG follow-up for life or until a full set of data are available to more accurately guide us as to when it may be safe to stop.

The optimal follow-up period for PSTT is less clear. The tumor is slow growing and therefore has the potential to relapse late. We have found that all of our patients have shown elevation of serum hCG levels in the presence of disease.30,33 However, it is possible that these tumors may fail to secrete hCG at relapse despite an extensive tumor burden.126 Consequently, patients in remission from PSTT should be followed serologically for life, and an argument could be made for regular review in the clinic. After treatment, patients should have baseline MRI of the pelvis and CT or MRI scans of other previously involved areas for future comparison in the event of a relapse. Timing of pregnancy after treatment and contraceptive advice. Patients are advised not to become pregnant

until 12 months after completing chemotherapy. This minimizes the potential teratogenicity of treatment and avoids confusion between a new pregnancy or relapsed disease as the cause of a rising hCG level Despite this advice, 230 women on follow-up at our center between 1973 and 1997 have become pregnant during the first year. Fortunately, this did not appear to be associated with an increased risk of relapse or fetal morbidity, and there were no maternal deaths.127 Seventy-five percent of women continued their pregnancies to term. Although we continue to advise women to avoid pregnancy for 1 year after completing chemotherapy, those who do become pregnant can be assured of a likely favorable outcome. When a patient becomes pregnant, it is important to confirm by ultrasound and other appropriate means that the pregnancy is normal. Follow-up is then discontinued until 3 weeks after the end of pregnancy, when the hCG level due to the pregnancy should have returned to normal. OCP use before the hCG level is normal after evacuation of a hydatidiform mole increases the risk of developing persistent GTD.74 For this reason, patients are advised to avoid OCPs until the hCG level has returned to normal after removal of a hydatidiform mole. Patients who have had chemotherapy for their GTT are advised not to use the OCP until their hCG level is normal and chemotherapy is completed.

Table 44–8. Follow-up of Low- or High-Risk Patients with Gestational Trophoblastic Tumors Treated with Chemotherapy Follow-up Period

Urine

Blood

Outpatient Follow-up

Year 1 First 6 wk 6 wk-6 mo 6 mo-1 yr Year 2 Year 3 Year 4 Year 5 Rest of Life

Weekly Every 2 wk Every 2 wk Monthly Every 2 mo Every 3 mo Every 4 mo Every 6 mo

Weekly Every 2 wk — — — — — —

6 wk after chemotherapy — — — — — — —

M a n a g e m e n t o f G e s tat i o n a l Tr o p h o b l a s t i c D i s e a s e 569 Figure 44–6. Arteriographic appearance of a uterine arteriovenous malformation before (left) and after (right) selective embolization in a patient with repeated vaginal hemorrhages after previous curative treatment for an invasive hydatidiform mole. The patient’s bleeding subsequently stopped, and she had a normal pregnancy in 1991.

Long-term complications of therapy. Most patients,

including those who have received intensive chemotherapy, return to normal activity within a few months, and most side effects, including alopecia, are reversible. Late sequelae from chemotherapy have been remarkably rare. In 15,279 patient-years of follow-up, there was no significant increase in the incidence of second tumors78 after MTX/FA therapy compared with matched controls (RR = 1.3; 95% CI: 0.6-2.1). Although similar results are not yet published for actinomycin D, this agent when used alone for the treatment of GTT also appears to be unlikely to induce second tumors (D. Goldstein, New England Trophoblastic Disease Center, personal communication, 2002). In contrast, 26 patients receiving combination chemotherapy for GTT developed another cancer when the expected rate was only 16.45, a significant difference.78 Second tumors included acute myeloid leukemia that was probably related to etoposide101,128-130 (RR = 16.61; 95% CI: 5.40-38.9; P < .000), colon cancer (RR = 4.59; 95% CI: 1.48-10.7; P < .005), melanoma (RR= 3.41; 95% CI: 0.03-8.75), and at 25 years after treatment, breast cancer (RR= 5.79; 95% CI: 1.19-16.86; P < .016). Consequently, women receiving multiagent chemotherapy must be warned of a small but significant increased risk of treatment-induced second tumors. Fertility is an important issue in the management of patients with GTTs. Neither MTX/FA nor EMA/CO affected fertility in our predominantly young population of women.131 Most women can be assured of a likely favorable outcome with regard to future fertility. However, women receiving EMA/CO after the age of 35 years sometimes fail to recover ovarian function. Chemotherapy does move forward the date of the menopause by about 1 year for MTX/FA and 3 years for EMA/CO.132 The psychological sequelae of the treatment has until recently been poorly investigated. Ngan and Tang133 found that women who had a molar pregnancy were less disturbed by the pregnancy loss if they subsequently required chemotherapy. Nevertheless, many

women become very depressed after completion of chemotherapy. During treatment, they probably have many different issues to focus on and receive lots of support from various members of staff, and this is lost after treatment is complete. After therapy is over, they often feel physically weakened. A study examining a range of quality of life issues in U.S. and British women treated 5 to 10 years earlier for GTT revealed that 51% would appreciate a counseling program today and that 74% would have appreciated counseling at the time of therapy.134 Nevertheless, our patients enjoy a good quality of life, with physical, social, and emotional functioning comparable to or better than comparative population norms.134 Is there a role for a nurse specialist? In the United Kingdom, both GTT treatment centers have employed a specialist nurse or nurse practitioner. This individual provides continuity of clinical service while junior medical staff rotate and provides counseling and psychological support, gives outpatient and community advice, and is a continuing link for the patient after therapy has been completed. The nurse practitioner also teaches formally and informally at a national and international level. Because the patients, general practitioners, and other medical attendants have all reported an improvement in the level of service, we believe that a nurse practitioner has provided a major advance. A fresh audit of this addition to the GTT service is under way, but it is clear that the employment of nurse practitioners in a variety of health services has led to striking improvements in the level of care delivery.135,136

Prognosis All patients in the low- and middle-risk groups can be expected to be cured of their GTTs.67,80,137 For highrisk patients, the survival rate has progressively improved and is currently 86%.79 The diagnosis of

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choriocarcinoma is often not suspected until the disease is advanced. As a result, some deaths occur before chemotherapy has a chance to be effective. The number of such patients can be diminished by a greater awareness of the possibility that multiple metastases in a woman of childbearing age may be caused by choriocarcinoma. The simple measurement of the hCG level in such individuals is a very strong indicator of choriocarcinoma and could help to hasten referrals for lifesaving chemotherapy. Summary In the past, many women died of GTD. However, during the past 50 years, we have learned much about the biology, pathology, and natural history of this group of disorders. Accurate diagnostic and monitoring methods have been developed together with effective treatment regimens. As a result, the management of GTD represents one of the modern success stories in oncology, with few women dying of their trophoblastic tumors.

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Figure 44–4. Ultrasonography with color Doppler shows persistent gestational trophoblastic disease after removal of a complete hydatidiform mole within the body and wall of the uterus. A typical vesicular or “‘snowstorm” appearance of residual molar tissue can be seen within the uterus together with a rich blood supply throughout the endometrium and myometrium. There is no evidence of a fetus.