Gestational trophoblastic neoplesia
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  • GTN can occur after any type of gestation. <br />
  • REFERENCE???? The combination of theca-lutein cysts and uterus larger than expected for dates increase the risk of postmolar GTN to 57%. <br />
  • The index pregnancy event may have occurred several years before presentation or may have been a subclinical spontaneous abortion. <br />
  • Use of the FIGO staging system is essential for determining initial therapy for patients with GTN to assure the best possible out comes with the least morbidity. <br />
  • Reference of mtx/act D regimens 1 and 5, how to give it?? <br /> Methotrexate 0.4 mg/kg/day given by intramuscular injection for 5 days, with cycles repeated every 12 to 14 days was the regimen originally used to treat GTN at the NIH. <br /> Significant hematologic suppression, cutaneous toxicity, mucositis, alopecia, gastrointestinal toxicity, and serositis are frequently seen in patients receiving this regimen. <br />
  • Craniotomy for resection of drug-resistant brain lesions is only rarely performed. <br /> craniotomy is reserved for women who require acute decompression of central nervous system hemorrhagic lesions, to allow stabilization and institution of therapy <br />
  • rarely virilization, nephrotic syndrome. <br />

Gestational trophoblastic neoplesia Gestational trophoblastic neoplesia Presentation Transcript

  • Gestational Trophoblastic Neoplasia Dr. Mohit Satodia GMCH-32 Chandigarh
  • Gestational Trophoblastic Neoplasia (GTN)  Trophoblastic diseases, a locally proliferative with ability to invade normal tissue, and the potential to metastasize.  Postmolar GTN  Invasive Mole  Choriocarcinoma  Placental Trophoblastic Tumor  Epithelioid trophoblastic tumor, a very rare subtype
  • Introduction  Most curable gynecologic malignancy.  Malignant GTD is diagnosed when there is clinical, radiologic, pathologic, and/or hormonal evidence of persistent gestational trophoblastic tissue.  Most commonly, the diagnosis is made following a molar pregnancy.
  • Postmolar GTN  50-66% of cases of GTN are postmolar. Symptoms Irregular bleeding following evacuation of a H. mole. Signs An enlarged, irregular uterus  Persistent bilateral ovarian enlargement.  A metastatic vaginal lesion may be noted on evacuation.
  • Risk Factors For Postmolar GTN  High pre-evacuation hCG levels > 1 lac  Uterine size larger than expected by dates.  Theca lutein cysts.  Increasing maternal age > 40 yrs
  • FIGO Diagnosis Of Postmolar GTN 1. Plateaued hCG (± 10%) 4 values over 3 weeks. 2. Rising hCG of (≥ 10%) 3 values over 2 weeks. 3. Persistence of hCG beyond 6 months after mole evacuation. 4. Histologically confirmed choriocarcinoma, invasive mole or PSTT. 5. Metastatic disease without primary site with elevated hCG (pregnancy has been excluded)
  • GTN Following Non-molar Gestations  Postpartum GTN : 1/50000 births.  History of irregular uterine bleeding, amenorrhea or recent pregnancy.  Hemoptysis, pulmonary embolism, cerebral hemorrhage, gastrointestinal or urologic hemorrhage or widely metastatic malignancy of an unknown primary site.
  • Whom to screen for non molar GTN ?  Woman with persistent vaginal bleeding after a pregnancy.  A urine pregnancy test should be performed.  Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely. (RCOG, 2010)
  •  The possibility of malignant GTN should be suspected in any woman of reproductive age who presents with metastatic disease from an unknown primary site or undiagnosed cerebral hemorrhage.  Under these circumstances the diagnosis is facilitated by a high index of suspicion coupled with serum hCG testing and exclusion of a concurrent pregnancy, most often without the need for tissue biopsy.
  • Gestational choriocarcinoma  Gestational choriocarcinoma is a pure epithelial malignancy, comprising both neoplastic syncytiotrophoblast and cytotrophoblast elements without chorionic villi.  1:50000 deliveries.  Gestational choriocarcinomas tend to develop early systemic metastasis and chemotherapy is clearly indicated when histologically diagnosed.
  • Route of metastasis  GTN usually spreads by hematogenous dissemination.  lymphatic spread uncommon
  • Evaluation of GTN  Complete history and physical examination.  Baseline hematologic, renal, and hepatic functions.  Baseline quantitative hCG level.  Chest X-ray or CT scan of chest if CXR is negative.  Brain MRI or CT scan.  CT scan of abdomen and pelvis. (AJOG,2010)
  •  Approximately 45% of patients present with metastatic disease when GTN is diagnosed.  Some pulmonary metastases result from deportation of trophoblast during molar evacuation and identification of pulmonary nodules in a post evacuation chest X-ray might not indicate true malignant behavior.
  • Metastatic site % Non-metastatic 54 Metastatic 46  Lung only  Vagina only  Central nervous system  Gastrointestinal  Liver  Kidney % Metastatic 81 5 7 4 1.5 0.7
  • Clinical Classification System For Patients With Malignant GTN Category Non-metastatic GTN Metastatic GTN Good prognosis metastatic GTN Poor prognosis metastatic GTN Criteria No evidence of metastases Any extrauterine metastases No risk factors Short duration (<4 months) Pretherapy hCG <40,000 mIU/mL No brain or liver metastases No antecedent term pregnancy No prior chemotherapy Any one risk factor Long duration (>4 months) Pretherapy hCG >40,000 mIU/mL Brain or liver metastases Antecedent term pregnancy Prior chemotherapy
  • FIGO score 2000 0 1 Age (years) < 40 ≥40 Antecedent pregnancy Hydatidiform mole Abortion Term pregnancy Interval from index pregnancy (months) <4 4 - <7 7 - <13 ≥ 13 Single drug ≥ 2 drug ≥ 100000 Previous failed chemotherapy 2 4 Pretreatment hCG (mIU/mL) < 1000 1000 - < 10000 10000 - < 100000 Largest tumor size including uterus (cm) <3 3-<5 ≥5 Site of metastases Lung Spleen, kidney GIT Brain, liver Number of metastases 0 1-4 4-8 >8
  •  Chest X-ray rather than chest CT would be used to assess the number of metastatic lesions.  Low Risk = ≤ 6  High Risk = ≥ 7
  • Treatment  Treatment is based on classification into risk groups defined by the stage and scoring system. (AJOG,2010)
  • Treatment of low risk GTN  Essentially all patients with this condition can be cured, usually without the need for hysterectomy.  Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score < 7) GTN can be treated with single-agent chemotherapy, with resulting survival rates approaching 100%. (AJOG,2010)
  •  Methotrexate is the corner stone of chemotherapy. Monitor Hematologic indices  Renal function test  Liver function test
  •  Oral methotrexate is readily absorbed via the GIT.  Barter reported a retrospective analysis of 15 patients treated solely with oral methotrexate 0.4mg/kg for 5 day cycles that were repeated every 14 days.  The primary remission rate was 87% with minimal toxicity  Concerns about patient compliance and the possibility of unpredictable absorption. Gynecol. 1987) (Barter, Am J Obstet
  • RCOG, 2010  Women are treated with single-agent intramuscular methotrexate alternating daily with folinic acid for 1 week followed by 6 rest days.  The cure rate for women with a score ≤ 6 is almost 100%.
  • AJOG,2010  Methotrexate most common side effect- stomatitis.  Actinomycin D has a more toxic side effect profile (nausea, alopecia) than MTX and produces local tissue injury if IV extravasation occurs.  Actinomycin D has most often been used as secondary therapy in the presence of MTX resistance or as primary therapy for patients with hepatic or renal compromise contraindicating the use of MTX.
  • Cochrane Review, 2012 July  Included five moderate to high quality RCTs (517 women)  Compared methotrexate with dactinomycin.  Three studies compared weekly IM MTX with bi-weekly pulsed IV DACT (393 women),  One study compared five-day IM MTX with bi-weekly pulsed IV DACT (75 women)  One study compared eight-day IM MTX-folinic acid (MTX-FA) with five-day IV DACT (49 women)
  • Contd..  Dactinomycin is more likely to achieve a primary cure in women with low-risk GTN, and less likely to result in treatment failure, compared with MTX.  There is limited evidence relating to side-effects, however, the pulsed DACT regimen does not appear to be associated with significantly more side-effects than the low-dose MTX regimen and therefore should compare favourably to the five and eight day MTX regimens in this regard.
  • Contd..  Review considers pulsed dactinomycin to have a better cure rate than, and a side-effect profile at least equivalent to, methotrexate when used for first-line treatment of low-risk GTN.
  • Abrao et al. Gynecol Oncol,2008 Jan  Comparison of single-agent methotrexate, dactinomycin and combination regimens.  Reviewed 108 cases with low-risk GTN who were treated with first-line chemotherapy.  42 patients MTX IM injection of 20 mg/m2 D1–D5  42 patients DACT IV infusion of 12 μg/kg a day D1–D5  24 patients both drugs with 20 mg MTX IM D1–D5 and with 500μg DACT IV infusion D1–D5.
  • Contd.. Complete remission  MTX 69%  DACT 61.4%  combination 79.1% (p=0.7) Adverse side effects 28.6% 19.1% 62.5% (p=0.0003)  The duration of the treatment and the number of chemotherapy courses were similar among the groups .
  • Contd..  Analysis indicates that single-agent chemotherapy regimens are as effective as combination chemotherapy for low-risk GTD.  Dactinomycin might offer the best cost-effective treatment option.  Methotrexate must be considered as the regimen of choice for low resource areas because of the feasibility of its administration.
  • Maintenance chemotherapy  Regardless of the treatment protocol used, chemotherapy is continued until hCG values have returned to normal and at least 1 course has been administered after the first normal hCG level.  When chemotherapy is given for an additional 1–2 cycles after the first normal hCG value,recurrence rates are <5%  Contraception, preferably oral contraceptives, should be used to prevent an intercurrent pregnancy during chemotherapy or monitoring after remission is achieved.
  • Role of surgery  Early hysterectomy will shorten the duration and amount of chemotherapy required to produce remission.  Therefore, each patient’s desire for further childbearing should be evaluated at the onset of treatment.  Hysterectomy may be performed during the first cycle of chemotherapy.  However, further chemotherapy after hysterectomy is mandatory until hCG values are normal.
  • Risk factors for drug resistance to single agent chemotherapy:  Older patient age > 35yrs  Higher hcg level > 1 lac miu/ml  Presence of metastatic disease  Higher figo score > 4 (AJOG,2010)
  •  Rate of fall of hCG levels has pateaued or values are rising during therapy should be switched to an alternative single agent regimen after radiographic restaging.  If there is appearance of new metastases or failure of the alternative single-agent chemotherapy, the patient should be treated with multiagent regimens.
  • Management
  • High-risk metastatic GTN  Patients classified as having high-risk metastatic disease (stage IV and stages II-III, score >6) should be treated in a more aggressive manner with multiagent chemotherapy ± adjuvant radiation or surgery to achieve cure rates of 80-90%. (AJOG,2010)
  • Regimens  MAC- MTX, DACT and cyclophosphamide or chlorambucil - 63-71% cure rate.  CHAMOCA - cyclophosphamide, hydroxyurea, actinomycin D, methotrexate with folinic acid, vincristine, and doxorubicin  In a RCT of CHAMOCA vs MAC, both the primary remission rate (65% vs 73%) and the ultimate cure rate (70% vs 95%) were inferior for CHAMOCA compared with MAC, and CHAMOCA was more toxic. 62) (Obstet Gynecol 1989;73:357-
  • EMA/CO  Alternating weekly chemotherapy with etoposide, methotrexate/folinic acid, dactinomycin/cyclophosphamide and vincristine (EMA/CO).  complete response rates 71-78% and long-term survival rates of 85-94%.  The most widely used regimen.  Toxicity- alopecia, stomatitis, emesis, Myelosuppression, neutropenia, anemia. No treatment-related deaths or life threatening toxicity occurred.
  • RCOG,2010  Women with scores ≥ 7 are at high risk and are treated with intravenous multi-agent chemotherapy, which includes combinations of methotrexate, dactinomycin, etoposide, cyclophosphamide and vincristine.  Treatment is continued, in all cases, until the hCG level has returned to normal and then for a further 6 consecutive weeks.  Cure rate for women with a score ≥ 7 is 95%.
  • EMA-EP  The regimen, substituting etoposide and cisplatin for CO in the EMA-CO protocol  Considered the most appropriate therapy for patients who have responded to EMA-CO but have plateauing low hCG levels or who have developed re-elevation of hCG levels after a complete response to EMA-CO.
  •  In patients who have clearly developed resistance to methotrexate containing protocols, drug combinations containing etoposide and platinum with bleomycin, ifosfamide, or paclitaxel have been found to be effective.
  • Recurrence  Approximately 30% of high-risk patients will fail first-line therapy or relapse from remission.  Salvage therapy with platinum-containing drug combinations, ± surgical resection of sites of persistent tumor, will result in cure of most of these high risk patients with resistant disease.
  • Role of surgery  Primary adjuvant hysterectomy not effective in reducing chemotherapy requirements or improving cure rates for women with high-risk metastatic GTN. (Hammond and colleagues)  Hysterectomy is effective in producing remissions in patients with chemoresistant non-metastatic or low-risk metastatic disease.
  • Management summarise:  Evaluate for high-risk metastases: brain, liver, kidney  Stabilize medical status of patient  Multiagent therapy with EMA/CO or MAC  At least three cycles of maintenance chemotherapy after hCG values normalize
  • Surveillance During And After Therapy Of GTN
  • Contraception  Contraception should be maintained during treatment and for 1 year after completion of chemotherapy, preferably using oral contraceptives.
  • Future Pregnancy  Because of the 1-2% risk of a second GTD event in subsequent pregnancies, pelvic ultrasound is recommended in the first trimester of a subsequent pregnancy to confirm a normal gestation, the products of contraception or placentas from future pregnancies should be carefully examined histopathologically, and a serum quantitative hCG level should be determined 6 weeks after any pregnancy.
  • Lung Metastasis  Radiographic evidence of tumor regression often lags behind hCG level response to treatment and some patients will have pulmonary nodules that persist for months or years after completion of chemotherapy.  Thoracotomy with pulmonary wedge resection- in highly selected patients with drug-resistant disease may successfully induce remission. Exclude the possibility of active disease elsewhere.  Prompt hCG level remission occurring within 1–2wks of surgery- a favorable outcome.
  • Brain Metastasis  8–15% of patients with metastatic GTN.  Brain irradiation with systemic chemotherapy.  During radiotherapy, the methotrexate infusion dose in the EMA-CO protocol is increased to 1g/m2 and 30 mg of folinic acid is given every 12 hours for 3 days starting 32 hours after the infusion begins. (AJOG, 2010)  A similar primary remission rate- high-dose systemic methotrexate with intrathecal methotrexate infusions, without brain irradiation.  Craniotomy
  • Contd.. Surgery1. To control hemorrhage from metastases. 2. To remove chemoresistant disease 3. To treat other complications in order to stabilize high-risk patients during therapy. 75–80% of women with brain metastases presenting for primary therapy and 50% of patients overall with brain metastases from malignant GTN will be cured.
  • Liver Metastasis  Involvement of the liver constitutes a poor prognostic factor.  Consider selective angiographic embolization or irradiation  Survival rates of 40–50% for women with primary liver involvement.
  • Vaginal Metastasis  Highly vascular.  Biopsy not recommended.  If vaginal metastases are the only site of metastasis, promptly respond to chemotherapy.  Vaginal packing or selective embolization to control active hemorrhage early in the course of treatment.
  • Hysterectomy  Hysterectomy performed when there is disseminated metastasis is unlikely to have a significant impact on the survival of patients with high-risk or recurrent GTN.  Ovarian removal is not required, as GTN rarely metastasizes to the ovaries and these tumors are not hormonally influenced.
  • Myometrial Resections Combined With Uterine Reconstruction  Patients with non-metastatic GTN not willing for hysterectomy.  Salvage procedures in women with localized chemoresistant disease.  Evaluate for systemic metastases and the uterine lesion using ultrasound, MRI, and hysteroscopy.
  • Contd..  Intraoperative frozen sections to assess surgical margins.  Small lesions associated with low hCG levels are more likely to be completely excised with a conservative myometrial resection than lesions >2–3 cm in diameter.
  • Invasive mole  Invasive moles are characterized by edematous chorionic villi with trophoblastic proliferation that invade directly into the myometrium.  Usually invasive moles undergo spontaneous resolution after many months but they are treated with chemotherapy to prevent morbidity and mortality caused by uterine perforation, hemorrhage or infection.
  • PSTT  0·2% of cases of GTD.  PSTT is a tumor of placenta implantation site.  Characterized by absence of villi with proliferation of intermediate trophoblast cells.  The syncytiotrophoblast is lacking with relatively lower levels of hCG. hCG is not a reliable marker of tumor volume.  Trophoblastic cells infiltrate the myometrium, and there is vascular invasion.
  •  Human placental lactogen (hPL) is present in the tumor cells.  Not as sensitive to simple chemotherapy as other forms of malignant GTN.  About 35% of PSTTs have distant metastases at diagnosis.
  • Epithelioid trophoblastic tumor  A rare variant of PSTT that simulates carcinoma.  Originally termed atypical choriocarcinoma, it appears to be less aggressive than choriocarcinoma and is now regarded as a distinct entity.  Appears to develop from neoplastic transformation of chorionic type intermediate trophoblasts.  Pathologically, it has a monomorphic cellular pattern of epithelioid cells and may resemble squamous cell cancer of the cervix when arising in the cervical canal.
  •  Most ETTs present many years after a full-term delivery.  Clinical behavior from benign to malignant.  About one-third of patients present with metastases, usually in the lungs. PSTT and ETT s/s Almost always irregular uterine bleeding often distant from a preceding nonmolar gestation.  The uterus is usually symmetrically enlarged.  Serum hCG levels are only slightly elevated.
  • AJOG,2010 Hysterectomy with lymph node dissection is the recommended treatment. Chemotherapy Metastatic disease  Nonmetastatic disease with adverse prognostic factors Interval from last known pregnancy to diagnosis > 2 years.  Deep myometrial invasion  Tumor necrosis  Mitotic count > 6/10 high power fields.
  •  Platinum-containing regimen, such as EMA-EP or a paclitaxel/cisplatin–paclitaxel/etoposide doublet, is the treatment of choice.  The survival rate is approximately 100% for nonmetastatic disease and 50-60% for metastatic disease.
  • Long-term Outcome Of Women Treated For GTN  Women who receive chemotherapy for GTN are likely to have an earlier menopause.  Women who require multi-agent chemotherapy which includes etoposide should be advised that they may be at increased risk of developing secondary cancers- acute myeloid leukaemia, colon cancer, melanoma, breast carcinoma. (RCOG,2010)
  • Thank you