Low Risk Disease Management
Our standard treatment for patients with low risk trophoblast disease is methotrexate given intra-muscularly with oral folinic acid rescue following the schedule shown below. The first course of treatment is administered in hospital, with the subsequent courses administered at home. However patients with a higher hCG level may need to stay in for longer as they have a higher risk of bleeding, particularly as the tumour shrinks rapidly with the initial chemotherapy. Bleeding usually responds well to bed rest and less than 1% of our low risk patients have required emergency interventions such as vaginal packing, embolisation or hysterectomy.
The low risk chemotherapy treatment is generally well tolerated without much major toxicity. Methotrexate does not cause alopecia or significant nausea and myelosuppression is extremely rare. Of the side effects that do occur, the most frequent problems are from pleural inflammation, mucositis and asymptomatic elevation of liver function tests.
For low risk patients with lung metastases on their chest X rays, our policy is to add CNS prophylaxis with intrathecal methotrexate (12.5mg) administration on 1 occasion if the CNS CSF is 1/60 of the serum hCG, no more intrathecal methotrexate is necessary.
2 weeks apart to minimise the risk of development of CNS disease (ref).
Results of treatment in low risk disease
The data shows that 67% of the low risk group patients will be successfully treated with methotrexate and we monitor their disease response by twice weekly serum hCG measurement. Following normalisation of the serum hCG level it is usual to continue treatment for another 3 cycles (six weeks) to ensure eradication of any residual disease that is below the level of serological detection (McNeish 2002).
Patients who have an inadequate response to methotrexate therapy as shown by an hCG plateau or rise have their treatment changed to second line therapy. This is single agent Actinomycin D Pulse, given 2mg IV every two weeks if the hCG is below 3000iu/L, or EMA/CO combination chemotherapy if the hCG is above 3000 iu/L.
An individual example of the pattern of hCG levels during the course of management is shown in Fig X. This demonstrates the rise in hCG that lead to the introduction of methotrexate chemotherapy, following this the hCG initally fell rapidly but after two cycles appeared to plateau. The introduction of second line treatment with EMA/CO chemotherapy lead to a rapid fall in the hCG to normal and the discontinuation of chemotherapy after 6 weeks further treatment. Overall the survival in the low risk group approaches 100% and the sequential introduction of additional chemotherapy as necessary minimises the potential long term carcinogenic risks of excess treatment.
High Risk Disease Management
Historical data that pre-dates the use of multi-agent chemotherapy schedules demonstrates that only 31% of the high risk patients would be cured with single agent chemotherapy (Bagshawe 1989).
The introduction of combination chemotherapy treatments in the 1970s transformed this situation and modern series shows a cure rate for high risk patients of 86% using EMA/CO chemotherapy (Newlands 1991, Bower 1997). This combination of drugs delivers a dose intense treatment with the 5 chemotherapy agents, delivered in two groups one week apart as shown in Table 3b. This approach to chemotherapy, rather than the more usual 3 or 4 weekly cycles used in other malignancies, appears to be the most effective approach to this rapidly proliferating malignancy. However, these drugs are fairly myelosuppressive and G-CSF support is frequently helpful.
Fortunately serious or life threatening toxicity is rare and the majority of patients tolerate treatment without any major problems. As in the low risk situation, treatment is continued for 6 weeks after the normalisation of the hCG.
Of the high risk patients treated with EMA/CO, approximately 17% develop resistance to this combination and require a change to second line drug treatment. In this situation we generally use the EP/EMA regimen as shown in Table 3c which incorporates cisplatin and a further dose of etoposide replacing the vincristine and cyclophosphamide. This treatment combined with surgery mostly to the uterus for defined areas of drug resistant disease, produces a cure rate approaching 90% in this relatively small group of patients (Newlands 2000).
With the aim of minimising short term infective risks and that of long term bone toxicity we avoid the routine use of dexamethasone in the anti-emetics, as this can be associated with both pneumocystis infection and avascular necrosis of the femoral head.
Approximately 4 % of patients presenting with trophoblast disease have cerebral metastases at the time of diagnosis. In contrast to most other malignancies where cerebral metastases are associated with a very poor prognosis, trophoblast patients with CNS disease can routinely be cured of their disease. Treatment may include an initial surgical resection if the disease is superficial and then chemotherapy with modified EMA/CO containing a higher dose of methotrexate, which enhances penetration into the CNS.
This treatment, combined with intra-thecal methotrexate administration, has produced a cure rate of 86% for patients with CNS disease who were fit enough at presentation to commence effective treatment (Newlands 2002).
The management of placental site trophoblast disease (PSTT)
The original description of placental site trophoblast disease suggested a relatively benign malignancy, however further data demonstrated that this is a malignancy that can often metastasise but can still be cured with effective therapy.
The management depends on careful staging, when the disease is limited to the uterus, curative treatment can be achieved with hysterectomy alone. For patients with disseminated disease we recommend treatment with EP/EMA chemotherapy, which is continued for 6-8 weeks after the normalisation of the hCG level. Following successful chemotherapy treatment we usually recommend hysterectomy. Our data for patients with PSTT treated between 1975 and 2001 demonstrates a 100% cure rate for those presenting within 4 years of the antecedent pregnancy, but a poorer prognosis for those presenting after a longer interval (Papadopoulos 2002).
EP/EMA (note the EMA in EP/EMA is the one day version) is the standard treatment for PSTT at CXH.
The role of CNS prophylaxis in PSTT is unclear. An approach based on the results of brain MRI and CSF/serum hCG ratio may be prudent.