Is there uniformity in definitions and treatment of gestational trophoblastic disease in Europe?

OBJECTIVES: Because gestational trophoblastic disease is rare, little evidence is available from randomized controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centers within countries. One of the goals of the European Organization for Treatment of Trophoblastic Diseases (EOTTD) is to harmonize treatment in Europe. To provide a basis for international standardization of definitions, treatment and follow-up protocols in gestational trophoblastic disease, we evaluated differences and similarities between protocols in EOTTD countries. METHODS: Members from each EOTTD country were asked to complete an online structured questionnaire comprising multiple-choice and multiple-answer questions. The following themes were discussed: incidence of gestational trophoblastic disease and gestational trophoblastic neoplasia, definitions, guidelines, classification system, treatment, recurrence, and follow-up. RESULTS: Forty-four respondents from 17 countries participated in this study. Guidelines were present in 80% of the countries and the FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) staging and risk classification was often used to estimate risks. Agreement about when to start chemotherapy for post-molar gestational trophoblastic neoplasia was present among 66% of the respondents. Preferred first-line treatments in low- and high-risk gestational trophoblastic neoplasia were methotrexate (81%) and EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) (93%), respectively. The definition of human chorionic gonadotropin normalization after hydatidiform mole evacuation was two consecutive normal values for nine countries. The FIGO definition of post-molar gestational trophoblastic neoplasia based on human chorionic gonadotropin plateau or rise was agreed on by 69% of respondents, and only 69% and 74% defined low-risk and high-risk disease, respectively, using FIGO criteria. There were major differences in definitions of recurrence, chemotherapy resistance and follow-up protocols among countries, despite EOTTD consensus statements. CONCLUSIONS: This questionnaire provides a good overview of current clinical practices in different countries. Based on the survey results, it is clear that there are several gestationaltrophoblastic disease-related topics that need urgent attention within the EOTTD community to create more uniformity and to aid the development of uniform guidelines in Europe.

Physicochemical stability of etoposide diluted at range concentrations between 0.38 and 1.75 mg/mL in polyolefin bags.

Introduction: According to the manufacturers, the diluted solution of etoposide should not exceed 0.4 mg/mL because precipitation may occur. For high doses or for patients requiring fluid restrictions, etoposide phosphate may be an option but shortages occurs frequently. The objective of this work was to study the stability of etoposide solutions between 0.38 and 1.75 mg/mL, diluted in 0.9% sodium chloride (0.9% NaCl) or 5% glucose (G5%) in polyolefin bags, stored at 25°C and between 2°C to 8°C, in a 61-day period. This study also observed the impact of an infusion pump on the physical and chemical stability of etoposide solutions. Materials and method: Chemical stability was analysed at days 0, 9, 16, 21, 28 and 61 by high-performance liquid chromatography. Physical stability was evaluated by visual and subvisual inspection. The action of an infusion pump on solutions was evaluated to verify the impact of the mechanical pumping action on the etoposide solutions. This investigation was performed at day 61, at the end of the study. Results: Etoposide solutions diluted at 0.38, 0.74 and 1.26 mg/mL in G5% and stored at 25°C were stable for 61 days and at 1.75 mg/mL for 28 days. In 0.9% NaCl, etoposide was less stable, with more precipitations observed. The action of an infusion pump has not caused any physical modifications. Conclusion: Storage at 25°C and G5% as diluent are recommended for etoposide high concentration with 61-day stability up to a concentration of 1.26 mg/mL and 28-day stability up to a concentration of 1.75 mg/mL. As a precaution, the use of an administration set with an in-line micro-filter is nevertheless recommended. Storage at 2°C to 8°C and the use of 0.9% NaCl increase the risk of precipitation.

Will BEACOPP be the standard for high risk Hodgkin lymphoma patients in advanced stages?

Hodgkin Lymphoma (HL) has become one of the most curable cancers, even in adulthood, through continuous improvement of therapeutic options and their verification by large multicenter trials. Today more than 95% of patients with HL in early stages and in advanced stages 85-90% can be cured. Nevertheless, these good results are threatened by treatment associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies. It is therefore the aim of future trial generations both to maintain the excellent treatment results and to minimize late effects. In 1964 for the first time deVita et al. described the MOPP polychempotherapy for patients with advanced HL which led to cure rates in more than 50%. Around ten years later Bonadonna et al. established the non cross resistant alternative regime to MOPP, ABVD which nowadays is accepted as "gold standard" for the treatment of advanced HL. MOPP and/or ABVD and furthermore the alternating MOPP/ABVD or the MOPP/ABV hybrid with and without the help of consolidative radiation resulted in around 70% long term survival rates, 30-40% of patients experienced tumor progression or relapses within 5 years. This led the German Hodgkin Study Group (GHSG) [Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 2003; 348: 2386-95] to improve the efficacy of COPP/ABVD by time- and dose-intensification, omission of Velban and Dacarbazin and adding Etoposide resulting in the BEACOPP principle. From the initial pilot studies in 1992 three trial generations, HD9, HD12, HD15, have now established this principle as one of the most effective chemotherapy regimen in advanced HL. We certainly hope that it will not last another 20 years to establish the BEACOPP regimen as an attractive curative treatment option for at least the high risk cohorts of HL.

Cemp, a mitoxantrone containing combination, in the treatment of intermediate and high grade non-hodgkin's lymphoma: an effective and non toxic therapeutic alternative for adult and elderly patients.

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occurred, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

Ifosfamide continuous infusion plus etoposide in the treatment of elderly patients with aggressive lymphoma: a phase II study.

A prospective phase II study was performed to evaluate efficacy and toxicity of continuous infusion ifosfamide plus etoposide combination in elderly patients (older than 70 years) with intermediate or high grade non Hodgkin's lymphoma. Chemotherapy was administered with mesna in order to avoid hemorrhagic cystitis. The 21 patients included were either unable to receive the usual front-line chemotherapy given in our institution or relapsing after or not responding to conventional chemotherapy. Only one out of 97 courses of chemotherapy was followed by serious complication consisting in non-lethal pneumonitis. Four out of seven previously untreated patients and five patients treated in first relapse achieved complete response (75 per cent). Out of nine refractory or previously multi-treated patients, only one achieved complete response. We conclude that combination of continuous infusion ifosfamide plus etoposide deserves to be evaluated on a larger scale so that the optimum doses and schedule may be defined.

High-dose Ara-C for remission induction and consolidation of previously untreated adults with ALL or lymphoblastic lymphoma.

Thirty-two patients with untreated ALL (n = 26) or lymphoblastic lymphoma (n = 6) between 17 and 65 years of age were treated with a short remission induction course with VP16-213, amsacrine, intermediate dose Ara-C for 6 days, prednisone and intrathecal methotrexate, followed by a consolidation course with vincristine, amsacrine, high dose Ara-C for 4 days, prednisone and intrathecal methotrexate. After subsequent cranial irradiation, no further maintenance was planned. However, some patients underwent an allogenic (n = 5) or autologous (n = 5) bone marrow transplantation after the consolidation treatment. Twenty-three of 32 patients (72%) achieved a complete remission. Ten of 13 patients with T-ALL or lymphoma, six of eight patients with pre-B or common ALL, and seven of 11 patients with B-ALL or Burkitt's lymphoma achieved a complete remission. The median duration of remission was 24 months. Overall survival for the whole group was 35% at 5 years. The disease-free survival was 45% at 5 years. Long-term survival for patients with B or T-ALL was approximately 60%, compared with 15% for those with common or pre B-ALL. Short term intensive courses including intermediate or high dose Ara-C during remission and consolidation treatment lead to results comparable to those obtained with long-term maintenance regimens. Our regimen may be sufficient for patients with T or B-ALL. Larger randomized studies are needed to investigate the relative importance of our observations.

Etoposide, ifosfamide and methotrexate combination chemotherapy in patients with aggressive non-Hodgkin's lymphoma after failure of the LNH 84 regimen.

We assessed the efficacy of an etoposide, ifosfamide and methotrexate combination therapy (VIM) in 24 patients failing the LNH 84 protocol. Eight of these patients were refractory to the LNH 84 induction regimen, 10 were partial responders and the six remaining attained complete response after LNH 84 induction but relapsed during consolidation therapy or after completing the whole programme. Twenty-three patients were evaluable for response. The VIM regimen provided a 43 per cent complete response rate and an additional 17 per cent partial response rate. The complete response rate was particularly high (67 per cent) in the group of patients who were partial responders to LNH 84 induction treatment. Of the 10 complete responders, five relapsed after 4 to 42 months and five are still alive with no evidence of disease after 27 to 60 months. Overall VIM was well tolerated. Myelotoxicity was the most common side-effect. Infections with fever were observed in 8 per cent of the VIM courses. This study demonstrates that a complete response and a long survival can be obtained in patients after failure of a high-dose doxorubicin containing front-line treatment.

Lomustine and melphalan cannot be replaced by cyclophosphamide and etoposide without reducing efficacy in MOPPEBVCAD chemotherapy for advanced Hodgkin's disease.

BACKGROUND AND OBJECTIVES: To evaluate the feasibility, toxicity and preliminary results of a potentially less toxic variant of the MOPPEBVCAD chemotherapy regimen for advanced Hodgkin's disease: MOPPEBVCyED, in which cyclophosphamide and etoposide replace lomustine and melphalan, respectively, with the remaining components being unaltered. DESIGN AND METHODS: The study was multicenter, prospective and randomized, and enrolled 67 patients with newly diagnosed stage IIB, III, IV Hodgkin's disease (62 were expected on the grounds of statistical considerations). Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. Median follow-up was 48 months. RESULTS: Comparing MOPPEBVCAD vs. MOPPEBVCyED, the results were as follows: complete remissions 35/35 vs. 30/32 (plus one partial remission and one disease progression); relapses 5 vs. 8; deaths 2 (one of myelodysplasia) vs. 2; delivered mean dose intensity (DI): lomustine 0.79+/-0.67 vs. cyclophosphamide 0.82+/-0.32; melphalan 0.80+/-0.13 vs. etoposide 0.86+/-0.18; average DI of the 7 drugs common to both regimens 0.73+/-0.10 vs. 0.83+/-0.11; all 9 drugs 0.75+/-0.13 vs. 0.84+/-0.09 (p=0.002); projected 5-year failure-free survival 0.79 vs 0.62; second cancers, two myelodysplasias vs. one carcinoma of the kidney. Toxicities were not statistically different except for heavier thrombocytopenia being recorded with MOPPEBVCAD. INTERPRETATION AND CONCLUSIONS: The higher cumulative and single drug DI recorded with MOPPEBVCyED may reflect better short-term tolerability, but it does not lead to better disease control. Its late toxicity may be expected to be lower in the future but at present it does not seem to be a sufficient reason to substitute MOPPEBVCyED for MOPPEBVCAD.