Trial Information

Vinblastine and Methotrexate in Children With Multivessel Pulmonary Vein Stenosis-A Phase II Study

We sought to develop a regimen that might successfully suppress myofibroblastic
proliferation in infants and children with progressive pulmonary vein stenosis. A number of
factors need to be considered when proposing novel treatment options for patients with
multivessel pulmonary vein stenosis. Specifically:

- Treatment should be directed against a specific target, in this case excessive
proliferation of myofibroblasts.

- Treatment should have known activity against the target cell.

- Treatment should be well-tolerated in the patient group. In this case, agents with
minimal hemodynamic side effects would be preferred.

- Treatment should not preclude patients from participation in other potentially
effective therapies. Specifically, agents that do not cause significant
myelosuppression would allow listing for transplantation.

- Treatment should not interfere with normal growth and development, and should have
minimal if any risk for long-term toxicity or second tumors.

After considering these factors, we chose to administer two chemotherapeutic agents,
vinblastine and methotrexate. Vinblastine and methotrexate have over 30 years of usage and
are well-tolerated. The agents used are given in low-dose and do not usually cause nausea or
vomiting, nor do they cause significant immunosuppression which, if present, could lead to a
risk of infection and fever.

Desmoid tumors, also referred to as infantile fibromatosis, overlap with infantile
myofibromatosis. A combination of standard agents that has been successfully used to treat
desmoid tumors in infants is vinblastine and methotrexate (24). As opposed to
cyclophosphamide-based regimens, this combination has the distinct advantages of few acute
side effects and no known long-term toxicities, such as infertility or second malignancy.
These agents have been used for over 30 years to treat infant and childhood malignancies.
Over the last five years, methotrexate and vinblastine have been used to treat 9 children
with recurrent desmoid tumor, a lesion similar although not identical to the abnormality
present in patients with pulmonary vein stenosis. This regimen had minimal acute toxicity
limited to mild to moderate nausea (which is easily controlled with anti-emetic therapy),
minimal alopecia, mild hepatic inflammation, and mild myelosuppression. An addition
advantage is that these drugs do not interfere with listing for lung transplantation, an
important factor in the overall treatment options for this patient population. Instead of
high-dose administration of chemotherapy (that catches only those cells in cycle at the time
of administration), the low-dose chronic weekly administration continues to catch
proliferating cells as they continually come into cycle. This may explain why the only other
trial of chemotherapy (with high-dose cytoxan) was unsuccessful. Of the 9 children with
desmoid lesions who received vinblastine and methotrexate therapy, four patients were
treated for 18 months or longer. At the time of the last report, no patient had progressive
disease during therapy. Two children had radiographically stable disease 1 and 2 years after
treatment. Two children had stable disease for 1 and 2 years after treatment and then had
disease progression. Thus, this drug combination is well-tolerated, has minimal side
effects, and has demonstrated clinical activity against a closely related type of lesion.