The Role of Local Therapy in Multi-focal Epithelioid Haemangioendothelioma

Results

Sixty-two patients with EHE presented to the Royal Marsden Hospital between 2000 and 2017 (Figure 1). Nine patients were excluded from the analysis due to follow-up in local hospitals. Twenty-nine of these patients received local treatments or active surveillance at the Royal Marsden Hospital, while 24 had systemic therapy. The outcomes in this group are reported in a separate publication (5). The median age was 41.5 years (range=16-72) in the local treatment group and 51 years (range=29-76) in those under surveillance (Table I). Liver and lung were the most common sites involved. Patient demographics and tumor characteristics at diagnosis are summarized in Table I.

Eighteen patients (34.0%) received local treatments for EHE, and 11 patients (20.7%) had active surveillance (Figure 1). Nine (50%) of the patients in the local treatment group had multi-focal disease at diagnosis, and all 11 patients in the surveillance group had multi-focal disease (Table I). Two patients in the surveillance group proceeded to have local therapy on disease progression. Primary resection was used in 10 patients, while other first-line treatment modalities in the local treatment group included radiotherapy (n=6), radiofrequency ablation (n=1), endovascular embolization (n=1), liver transplant (n=1) (Table II). Further lines of local treatments used were metastasectomy (n=1), irreversible electroporation (n=1), and re-excision (n=2, with one patient undergoing two further re-excisions following primary surgery). Details of treatment and outcome can be found in Table III.

Surgery +/− other local treatment (n=10). Two (20%) patients in this group had multi-focal disease at the time of diagnosis. Ten patients had primary resection for EHE, and six did not require further treatment after a median follow-up of 27.5 months. Two patients needed further re-excision of the primary site. The first patient had residual disease excised and was found to have positive regional lymph nodes which were unresectable. The patient then underwent active surveillance, and is well 25 months following the re-excision with no recurrence at the primary site and stable appearance of the nodal disease. The second patient, who had multifocal disease at the time of first surgery, had two further re-excisions of the primary sites following local disease progression at 4 months and 18 months, respectively, from the first operation, ultimately resulting in an above-knee amputation. The disease is stable in the lung and liver 6 months following the above knee amputation.

Of the 10 primarily surgically managed patients, eight (80%) were free of local recurrence with a median follow-up of 31 months (range=2-56). Local recurrence was found in two patients (20%), with a median PFS of 9.5 months. One patient was treated with surgical re-excision as described above and the other with irreversible electroporation (IRE). The other patient had multi-focal disease in the lung and liver and was treated with IRE to the enlarging liver tumors 15 months after primary resection. IRE was performed in two metastases measuring 5.4 cm and 3.2 cm. The patient is progression-free 9 months following the procedure. Patient No. 2 in Table III had residual disease excised upon review of post-operative pathology and was therefore not deemed to have local recurrence. This patient had residual disease excised and is free of recurrence at the 35-month follow-up.

Nine (90%) patients had no evidence of distant recurrence with a median follow-up of 24 months. One patient developed distant recurrence in the liver and underwent metastasectomy 7 months following primary surgery. He is now recurrence-free, 23 months after the procedure.

All 10 patients were alive at the time of analysis, with a median follow-up of 27 months.

In terms of toxicity, one patient developed a seroma post-operatively which was drained, and another patient developed post-operative chronic pain following primary resection of an upper limb EHE requiring ongoing input from the pain team. Other local treatments without primary surgery (n=8). All patients had multi-focal disease at diagnosis. One patient had liver transplantation, six had radiotherapy, one had endovascular embolization followed by proton therapy, and one had radiofrequency ablation. Five patients developed local recurrence (median local PFS= 8 months), and two patients received systemic treatment, two underwent surveillance, and one had surgical excision. Three (37.5%) patients remained disease-free at 21 months median follow-up. Two patients had distal progression (median distal PFS=10.5 months), one was started on systemic treatment and the other on surveillance. Six (75%) remained disease-free at 37 months median follow-up. Four (50%) patients were alive at the time of analysis (median follow-up= 44.5 months), four had died at the time of analysis and had a median OS of 36.5 months. No significant adverse events were recorded.

One patient had multi-focal disease in the liver and underwent liver transplant one year following diagnosis. She subsequently developed multi-focal liver lesions 31 months post-transplant which slowly increased in size. She eventually had a partial hepatectomy after 18 months of surveillance due to an increase in the size of the lesions, and is recurrence-free at 11 months post-op (72 months follow-up).

One patient underwent endovascular embolization 10 months following diagnosis. The patient then received proton therapy two months following endovascular embolization (<18 years old at diagnosis). The patient developed metastasis one month following completion of proton therapy and received chemotherapy (doxorubicin/ ifosfamide for three cycles, followed by paclitaxel on progression). She passed away five months after starting chemotherapy (OS=21 months).

A patient with disease in the liver, lung, retroperitoneum and bone was treated with RFA to a liver lesion (6 months from diagnosis). There was evidence of local progression in the liver 7 months following RFA. She was started on celecoxib and died 2 months later (OS=15 months).

The two patients described above both developed pleural effusion and the time from event to death was 6 and 2 months respectively.

Radiotherapy was given to six patients for bone metastases. Two received radical treatment one of which was delivered via stereotactic ablative technique and one had proton therapy (outcome described above). The patient with stereotactic ablative radiotherapy had a local PFS of 62 months and on recurrence was given chemotherapy. The patient has stable disease at 11 months follow-up. Among the four patients receiving conventional RT, whilst one did not develop further disease-events (median follow-up 52 months), two patients developed local recurrence (PFS 8 and 9 months respectively) and one developed distant progression at 20 months. These were all managed with active surveillance.

Surveillance group (n=11). Eleven patients with multi-focal disease at the time of diagnosis were treated conservatively with active surveillance. Six patients had progression in primary disease sites with a median PFS of 29 months. Of these six, two patients continued on surveillance, one was referred for liver transplant and one for IRE. Two were started on chemotherapy. Three patients in the surveillance group developed pleural effusion. In the surveillance group, there was no progression in five (45.4%) patients (median follow-up 29 months), and no distal progression in any patient. Six (54.5%) patients were alive at the time of analysis (median follow-up 35 months). Five had died at the time of analysis (median OS=29 months), and two of the five deaths were unrelated to malignancy.

Pleural effusion appeared to be a poor prognostic factor in EHE. Among patients treated with local therapy or surveillance, it was present in five (9.4%) patients. Three patients had systemic treatment and two were treated conservatively. All five patients had died at time of analysis with a median time from development of pleural effusion to death of five months.