Trabectedin in Advanced High-Grade Uterine Leiomyosarcoma: A Case Report Illustrating the Value of 18FDG-PET-CT in Assessing Treatment Response
A 60-year-old woman presented following 2 episodes of postmenopausal bleeding, several months apart. The patient had no significant medical, surgical or family history, was on no medication and with all previous screening investigations reported as normal. Initial trans-abdominal and trans-vaginal ultrasound scans demonstrated appearances which were felt to be consistent with uterine fibroids. A subsequent CT scan confirmed a large (80 μ 60 mm) heterogeneously enhancing but predominantly hypo-dense mass within the uterus, extending deeply, with only a very thin layer of normal myometrium. There were no enlarged lymph nodes and no evidence of local or distant disease spread. Endometrial chippings obtained by Pipelle biopsy demonstrated a high-grade sarcoma, with a mitotic count of 15 per 10 high-powered fields. Cells were positive for vimentin, strongly positive for oestrogen receptors and moderately positive for progesterone receptors. Staining for cytokeratin, actin, myoD1 and CD10 was negative. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed, following which histology confirmed a high-grade, undifferentiated sarcoma of the uterine corpus extending deeply into the myometrium and reaching up to the serosa.\nLymphovascular invasion was present and the mitotic count was high, at 42 per 10 high-powered fields. There was no evidence of malignancy affecting the fallopian tubes, ovaries, cervix or the single pelvic lymph node removed. Peritoneal washings were negative for malignancy. This was reported as an International Federation of Gynaecology and Obstetrics (FIGO) stage 3a high-grade uterine sarcoma []. Following surgery, the patient commenced a course of adjuvant chemotherapy, receiving five 3-weekly cycles of the combination of doxorubicin (50 mg/m2) and ifosfamide 5 g/m2 (1,700 mg/m2 on days 1, 2 and 3). Repeat CT imaging of the chest, abdomen and pelvis was performed on completion of adjuvant chemotherapy and, again, 26 months after surgery. On neither scan was there any evidence of metastatic disease. At a routine review 31 months after surgery, the patient described a short history of new pelvic discomfort although she remained well, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Magnetic resonance imaging (MRI) of the pelvis confirmed a large (7.5 μ 5 cm) heterogeneous mass in the anterior pelvis, indenting the bladder, with 2 soft tissues nodules (3 μ 2.3 and 1.6 μ 1.4 cm) in the pelvis. A subsequent CT scan demonstrated new pulmonary metastases and a bone metastasis in the T7 pedicle.\nOn confirmation of metastatic disease, and in view of the strongly positive staining for oestrogen receptors on the original histology, the treatment selected was a trial of the aromatase inhibitor letrozole (2.5 mg). However, CT reassessment after 8 weeks of therapy demonstrated a marked increase in the size of the pelvic masses, along with minor increases in the sizes of both the pulmonary and T7 metastases. There was new metastatic involvement of the L3 pedicle. An 18FDG-PET-CT scan confirmed the disease was moderately FDG avid and revealed multiple additional sites of skeletal involvement, including the right scapula, left sixth rib and right acetabulum. The multiple pelvic masses were described as being confluent and part solid, part cystic, with a maximum axial dimension of 13 cm. The cystic components were FDG negative, whilst the most FDG-avid soft tissue component was located medial to the right external iliac vessels, with a maximum standardized uptake value (SUVmax) of 9.4.\nConsidering disease progression with letrozole, trabectedin was commenced at an initial dose of 1.5 mg/m2 administered as a 24-hour intravenous infusion every 3 weeks. Each infusion was preceded by 500 ml 0.9% sodium chloride and 20 mg dexamethasone intravenously. Treatment was tolerated well with grade 2 fatigue and grade 1 nausea, responding to oral cyclizine, being the worst trabectedin-related adverse events. The patient's ECOG performance status continued to be 0 for at least half of every cycle and was never greater than 1. After 3 cycles of trabectedin, a further 18FDG-PET-CT scan was performed to assess initial response to therapy (fig. , right panel). The pulmonary disease was stable and the skeletal deposits had marginally increased in avidity. There was a marked increase in the size of the pelvic mass, with expansion of the cystic component, such that the maximum diameter was now 20.1 cm. However, there was an associated reduction in the SUVmax of the solid component of the pelvic mass, indicating a cystic or necrotic response in the tumour to trabectedin, with the site of most active disease displaying reduced FDG uptake. No new lesions were identified. Taking into consideration the response detected by PET-CT, treatment continued with trabectedin.\nFollowing 3 cycles, the frequency of administration was reduced to 4-weekly, and after 6 cycles the dose was reduced to 1.3 mg/m2. Each change was made in response to escalating fatigue (>grade 2). A pelvic ultrasound scan after the sixth cycle of trabectedin suggested a subjective interval decrease in the solid peripheral component of the pelvic tumour. Yet, before the patient could proceed to cycle 7 she was admitted for acute abdominal pain and vomiting. At this stage a repeat pelvic ultrasound scan revealed that the complex pelvic mass had collapsed, with crenation of the peripheral margin and new moderate-volume generalized ascites. A total of 3.7 litres of sero-sanguinous fluid was drained with marked symptomatic relief, and the patient was discharged home after 48 h with no treatment delays. A further 2 cycles of trabectedin 1.3 mg/m2 were administered at 4-weekly intervals, following which reassessment of the extent of disease was made. Interpretation was complicated by the pelvic cystic collapse and subsequent drainage, altering tumour size and by implication any response measure as per RECIST. However, on 18FDG-PET-CT there was clear evidence of ongoing disease improvement after 7 months of treatment with trabectedin (fig. ). The lingular pulmonary metastasis had reduced in size and become FDG negative, and there was further reduction in the size of a second left upper lobe pulmonary metastasis. The bony metastases were stable. The solid pelvic components were at worst stable, with an unchanged SUVmax, and possibly marginally reduced in size. The patient continued on trabectedin 1.3 mg/m2, 4-weekly, finally showing signs of progression on an 18FDG-PET-CT scan performed after a total of 13 cycles of treatment, administered over 13 months. The safety profile of trabectedin remained manageable, showing no evidence of cumulative toxicity, maintaining quality of life. Fatigue resulted in an ECOG performance status that fluctuated between 0 and 1 during the treatment.\nAll procedures were conducted in accordance with the Declaration of Helsinki, guidelines for good clinical practice and local regulations, and were approved by the institutional review board. Signed informed consent was obtained from the patient.