Current therapies for metastatic or relapsed Ewing sarcoma have not substantially improved outcomes in this high-risk population with five-year survival rates < 20% 1
. Graft-versus-malignancy reactivity clearly contributes to the curative potential of allogeneic stem cell transplants (SCT) for leukemias and lymphomas, however the utility of allogeneic SCT for solid tumors remains controversial. Evidence for a graft-versus-tumor effect comes primarily from metastatic renal cell carcinoma 2
, however responses have been reported in sarcomas, including a graft-versus-Ewing effect 3–6
. Here we report a case of disease stability followed by an unusual pattern of recurrence in a Ewing sarcoma patient following reduced intensity allogeneic SCT.
A 26-year-old male initially presented with a 4-month history of left thigh pain and a palpable thigh mass. MRI revealed a 17 × 17cm mass arising from the left lateral femur, complicated by pathologic fracture. Needle biopsy revealed a Ewing sarcoma with no metastases noted on presentation. The patient received standard five-drug therapy (cyclophosphamide, doxorubicin and vincristine alternating with ifosfamide and etoposide) with local control consisting of 5580cGy radiation to the femur. At the completion of initial therapy there was no evidence of disease. One year later, a routine restaging chest CT revealed pulmonary metastasis and a left hilar lymph node (). The remainder of re-staging was negative including bone marrow biopsy. The patient received 4 cycles of cyclophosphamide and topotecan, during which time the pulmonary lesions progressed (). He was then enrolled on an IRB-approved, reduced intensity, allogeneic SCT protocol for patients with ultra-high risk pediatric sarcomas. Three cycles of induction chemotherapy with EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) were given for immune depletion and disease control, during which the pulmonary disease was stable with no new lesions. His preparative chemotherapy prior to SCT comprised of fludarabine, cyclophosphamide and melphalan followed by infusion of unmanipulated, G-CSF mobilized peripheral blood stem cells from a fully matched sibling on day +0. GVHD prophylaxis consisted of cyclosporine monotherapy. Myeloid engraftment occurred on day +10 with full donor chimerism by day +14. On day +19 he developed biopsy-proven acute GVHD of the skin and liver. Methylprednisolone was initiated, cyclosporine was discontinued, and tacrolimus was started. There was a complete response and methylprednisolone was tapered and discontinued on day +58, and tacrolimus was discontinued on day +91 (). During this time, CT scans of the chest revealed stable or shrinking lung nodules, although not sufficient to meet NCI RECIST criteria. However, biopsy confirmed the presence of active tumor. Lymphocyte reconstitution showed an initial rise at day +28, with a decrease in B and T cells during steroid administration, and then continued to recover after day +60 steadily (). Naïve and memory T cells demonstrated a similar decline with GVHD therapy followed by a rise in naïve CD4 T cells by day +100 that were sustained ().
Figure 1 Pulmonary metastases to the left hilum and left lower lobe as shown by chest CT post-contrast, (A) starting at initial recurrence, and (B) at pre-SCT restaging after 4 cycles of cyclophosphamide and topotecan. (C) Followed over the length of the SCT, (more ...)
Approximately three months post-SCT, the patient experienced a 15-minute seizure. A brain MRI demonstrated three hemorrhagic lesions consistent with metastases (). He subsequently received 2950cGy whole brain radiation with complete resolution of his lesions. Six months post-SCT, the left parenchymal and hilar metastases demonstrated very slow progression () and he was placed on a 3-month trial of sirolimus for potential antitumor activity 7
and for management of limited, mucosal chronic GVHD. The patient had continued slow progression of pulmonary disease and at ten months post-SCT he received one cycle of reduced-dose EPOCH, complicated by anorexia, weight loss, and a one-month history of vague intermittent abdominal cramps with intermittent diarrhea. An abdominal CT revealed an ileocecal intusseception with a mass at the lead point (). He underwent ileocecectomy, removing 20cm of ileum, and had a segmental resection of the mid-jejunum (). Surgical pathology showed his masses to be Ewing sarcoma. He received oral etoposide postoperatively, with no response, and subsequently died of progression on day +454 post-SCT.
Figure 2 Ewing sarcoma metastases (A) to the left parietal lobe and right occipital lobe as visualized by MRI T2 post-FLAIR, (B) serving as a lead point for an ileocecal intussusception seen by abdominal CT post-contrast (C), and during exploratory laparotomy. (more ...)
We believe this case provides important observations regarding allogeneic SCT for Ewing sarcoma. First, reduced intensity conditioning is well tolerated in this high-risk patient population. Second, although Ewing sarcoma classically metastasizes to the lung, bone, and bone marrow, this patient recurred in two highly unusual metastatic sites, the brain and small intestine, following allogeneic SCT. Hematogenous brain metastases occur in as many of 40% of adult patients with solid malignancies but are uncommon in children with solid tumors, with one review reporting an incidence of 3.3% in Ewing sarcoma 8,9
. Although there have been case reports of Ewing sarcoma occurring as a primary lesion of the small intestine, our review of the literature demonstrates this to be the first report of Ewing sarcoma metastasizing to the small intestine 10–13
. Thus, we believe the occurrence of 2 highly unusual sites of metastasis in the same patient following allogeneic SCT may represent modulation of the disease by alloreactivity. While the timing of his metastases coincide with treatment of GVHD, which would suppress host immunity and perhaps allow metastases to sanctuary sites, there was also a period of relative stability of his pulmonary masses during the treatment of GVHD, despite pathologic confirmation of active tumor. Although this may be initially due to a conditioning regimen effect, the length of stability in a patient (218 days) who was previously rapidly progressing and refractory to salvage chemotherapy, suggests a degree of tumor control by the SCT. Interestingly, this progression occurred despite a very early recovery of naïve CD4+
T cells, which would be predicted to contain a broad repertoire of specificity 14
. Strategies to direct immune responses toward the tumor using vaccines may be ideal in this setting.
Alterations in metastatic patterns may be due to prolonged survival, alteration of the host environment or the introduction of the donor immune response, forcing the tumor to escape in unusual sites. Allogeneic SCT may represent a platform from which to manipulate and enhance the anti-tumor immune response. Whether this offers an inherent advantage over approaches to induce an autologous anti-tumor immune response remains to be seen 15