Shreyaskumar R. Patel, MD: Main Indication for Dose Reduction

What are the main indications for dose reduction in patients on trabectedin?

If you go back to the phase III registrational clinical trial that just recently got published in theJournal of Clinical Oncology, the dose reduction guidelines were left to the treating physician and the investigators in some ways. The drug isn’t very well tolerated. The dose limiting toxicities again can be hematologic or non-hematologic. The hematologic toxicities are neutropenia or neutropenic fever, but an occasional patient can even see some severe thrombocytopenia. A lot depends upon how heavily they have been treated prior to initiation of Yondelis. So the dose reduction for hematologic toxicities is again left to the discretion of the treating physician.

There are patients who will have a transient drop in their platelet count to 20,000 but recover quickly. Even if they needed a platelet transfusion, as long as there were no consequences of that, one could maintain the same dose to get the maximum benefit. On the other hand, if the clinical judgment suggested that this is a fragile patient and the risks were high, you could dose reduce by one level from 1.5 mg down to 1.2 mg, for example. Similarly for febrile neutropenia, as well.

If the episode was uncomplicated, it’s the clinician’s decision as to whether dose reduction in that given patient is absolutely mandatory or can the patient maintain the same dose to get the maximum benefit. The non-hematologic toxicities are a little different, I think the liver toxicities in particular. The transaminitis that patients could get can create some life-threatening situations. Liver toxicity in terms of transaminitis, elevated bilirubins or an obstructed pattern with elevated alkaline phosphatase is taken a lot more seriously, I think, because that clearly can have some life-threatening implications for that given patient.

CASE: Soft-Tissue Sarcoma Case 2

Michael C is a 59-year-old social worker from Los Angeles California; his medical history is notable for obesity, COPD, and mild hypertension.

• In January of 2014, he presents to his PCP with complaints of right lower leg pain of several weeks’ duration
• Physical exam was unremarkable except for swelling of the lower right calf; x-ray of the affected leg was negative for fracture
• MRI scan of the lower right calf showed a 20 cm well defined lobular mass arising between the gastrocnemius and soleus
• Biopsy of the mass showed myxoid liposarcoma with round cell component. Patient underwent en bloc resection of the tumor following preoperative radiotherapy
• Gross examination showed the tumor to be 10 × 8 × 15 cm with gelatinous brownish appearance

In September of 2014, Michael returns for follow up and his CT scan shows a 4 cm posterior mediastinal mass, and a 6 cm perinephric mass suspicious for metastatic disease. He initiates treatment with anthracycline and ifosfamide chemotherapy (6 cycles) for recurrent disease and shows a partial response.

• In May of 2015, he returns for follow up with intermittent chest and lower back pain; CT scan is consistent with progression of the mediastinal and perinephric masses, and bone scan shows new lesions occurring in the L2 and L3 lumbar vertebrae
• At recurrence, liver and renal function and CBC are within normal limits, and his ECOG performance status is 1
• He received treatment with trabectedin (1.5 mg/m2 24-hr infusion given every 3 week)
• At the 2nd cycle he develops febrile neutropenia (ANC< 500 cells/mm3) requiring hospitalization
• The oncologist reduces his trabectedin dose to 1.2 mg/m2; he continues therapy
• Within 1 week, he shows clinical improvement and CT scan shows slight improvement