Is it Time to Change the Standard of Care for Low-risk GTN?

Abstract & Commentary

By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.

Dr. Coleman reports no financial relationship relevant to this field of study.

Source: Osborne RJ, et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: A gynecologic oncology group study. J Clin Oncol 2011;29:825-831.

Synopsis: Biweekly dactinomycin produced a higher complete response rate, required half the number of treatment cycles, and was associated with earlier recognition of treatment failure relative to weekly methotrexate in women with low-risk gestational torphoblastic neoplasia.

There are at least six different commonly used chemotherapeutic regimens in practice to treat patients with low-risk gestational trophoblastic neoplasia (GTN) with no consensus or previous formal evaluation as to which may be best. The Gynecologic Oncology Group (GOG) sought to examine two commonly used regimens: methotrexate (30 mg/m2 administered weekly, intramuscularly) or dactinomycin (1.25 mg/m2 administered biweekly, intravenously) in women meeting "low-risk" criteria (see Table). The primary endpoint for this randomized Phase 3 study was complete response (CR), defined as resolution of quantitative bhCG to 0 mIU/mL (or equivalent institutional normal). Overall, 240 women were enrolled over 7.5 years; 216 were evaluable for the primary endpoint. The overall CR rate for women receiving dactinomycin was significantly higher than those receiving methotrexate (70% vs 53%, P = 0.013). Success with either treatment was reduced in women with higher World Health Organization (WHO) scores and those with choriocarcinoma, but still favored dactinomycin. The average number of cycles administered to women with a CR was 8 for methotrexate and 4 for dactinomycin (total treatment time was an average of 8 weeks). Patients who did not achieve CR were subsequently managed with alternative chemotherapy, surgery (hysterectomy), or both. Two patients (one in each arm) had a potential recurrence following CR. All patients for whom long-term follow-up was available were cured of their disease. No patients were removed from study treatment due to toxicity and, in general, both treatments were well tolerated. The authors conclude that dactinomycin is associated with a higher CR rate relative to methotrexate in low-risk GTN.

Commentary

GTNs are rare malignant transformations of gestational trophoblastic tissues arising from the fetal chorion and most frequently are associated with an antecedent complete hydatidiform molar pregnancy.1 They also may occur after a normal pregnancy or even more uncommonly following a partial hydatidiform molar pregnancy. They are part of the spectrum of gestational trophoblastic disease (GTD), which, in addition to molar pregnancy (complete and partial), also includes placental site trophoblastic tumor, epithelioid trophoblastic tumor, and choriocarcinoma. GTN is a disease in which a diagnostic biopsy is not required, and is predominately declared by lack of biomarker (bhCG) resolution in surveillance. The criteria of what constitutes an aberration have changed some in the last decade (see Table); patients meeting the diagnosis are then "staged." The current GTN staging system combines FIGO anatomical staging with a composite score (Modified WHO Prognostic Scoring System) based on age; parameters of antecedent pregnancy event (type and duration to diagnosis); bhCG level; tumor location, size, and number; and previous treatment (if any).2 Low-risk disease (WHO scores of 0-6) is highly curable with single-agent chemotherapy, several of which are touted. The current study was undertaken to assess two popular strategies: weekly IM methotrexate and biweekly IV dactinomycin. The primary endpoint was CR, which was demonstrated to be superior in the dactinomycin arm. It also was associated with fewer treatment cycles and superior activity among higher WHO scores and patients with choriocarcinoma. The trial spanned the 2002 amended WHO classification criteria, which designated patients with WHO scores of 5 or 6 as "low risk." In response, the trial was amended to include these patients (n = 17 or 8% of the treatment population) in the randomization. It is clear from this report that methotrexate 30 mg/m2 IM is not acceptable therapy for these patients. However, tolerance and compliance were high with both strategies and all patients completing follow-up were cured, predominately by either switching over to the alternate arm, receiving multiagent chemotherapy, surgery, or some combination of these.

Table. Diagnostic Criteria for Gestational Trophoblastic Neoplasia (GTN)

Criteria Pre-2002 Post-2002
Declining bhCG (amount - time) < 10% over 3 weeks (4 values) Same
Rising bhCG (amount - time) > 20% over 2 weeks (3 values) > 10% over 2 week (3 values)
Persistent bhCG (time) > 4 months > 6 months
Choriocarcioma Yes Same
Metastatic Choriocarcinoma Vaginal -
  Lung < 2cm (No computed tomography)  
  Parametria  

The question remains as to whether methotrexate (the treatment standard for "low-risk" GTN) should be replaced by the more active dactinomycin. Although on the surface the substitution would seem warranted, several factors should be considered. The first relates to the methotrexate dose and administration. The experience from several institutions, including trophoblastic centers, report much higher cure rates with this agent administered at higher doses and in different infusion schedules.3 This has been a major criticism of the trial despite previous experience from the GOG demonstrating the absence of a dose-response in "low-risk" GTN. A second major concern is safety. Methotrexate has a large body of safety data upon which to draw questions about long-term effects on inducible (secondary) malignancy and fertility preservation.4 At this point there is no comparative data set for patients treated with dactinomycin, which under common infusion schedules may be associated with myelosuppression, alopecia, and nausea. Further, although short-term adverse events were similar between the cohorts in this study, the margin of error for dactinomycin is narrower, as the agent is a strong vesicant and is most safely administered via central venous access. In general, our practice is to continue to treat patients with methotrexate either with daily treatment for five days or every other day with leucovorin rescue, and reserve dactinomycin for low-risk patients in whom this treatment has failed. Future randomized trials will investigate more contemporary methotrexate regimens, including better pretreatment imaging and more precise pretreatment stratification.

References

  1. Schorge JO, et al. Management of low-risk gestational trophoblastic neoplasia in indigent women. J Reprod Med 2003;48:780-784.
  2. Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynecol Obstet 2009;105:3-4.
  3. McNeish IA, et al. Low-risk persistent gestational trophoblastic disease: Outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002;20:1838-1844.
  4. Rustin GJ, et al. Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors. J Clin Oncol 1996;14:2769-2773.