However, the pivotal study did show a significant difference between two different trabectedin treatment regimens, and due to the rarity of the disease, the CHMP considered that marketing authorization could be granted under exceptional circumstances. As part of the approval PharmaMar agreed to conduct a further trial to identify whether any specific chromosomal translocations could be used to predict responsiveness to trabectedin.Trabectedin is also approved in South Korea and Russia.In 2015, (after a phase III study comparing trabectedin with dacarbazine), the US FDA approved trabectedin (Yondelis) for the treatment of liposarcoma and leiomyosarcoma that is either unresectable or has metastasized. Patients must have received prior chemotherapy with an anthracycline. Ovarian cancer and other
In 2008, the submission was announced of a registration dossier to the European Medicines Agency and the FDA for Yondelis when administered in combination with pegylated liposomal doxorubicin (Doxil, Caelyx) for the treatment of women with relapsed ovarian cancer. In 2011, Johnson & Johnson voluntarily withdrew the submission in the United States following a request by the FDA for an additional phase III study to be done in support of the submission.Trabectedin is also in phase II trials for prostate, breast, and paediatric cancers. Structure
Trabectedin is composed of three tetrahydroisoquinoline moieties, eight rings including one 10-membered heterocyclic ring containing a cysteine residue, and seven chiral centers. Biosynthesis
The biosynthesis of trabectedin in Candidatus Endoecteinascidia frumentensis starts with a fatty acid loading onto the acyl-ligase domain of the EtuA3 module. A cysteine and glycine are then loaded as canonical NRPS amino acids.
However in "A Report From an International Consortium", the authors analyzed patient data from the Childrens Oncology Group (COG) and European paediatric Soft tissue sarcoma Study Group (EpSSG), hoping to identify and analyze any relationship between clinical outcomes and genetic mutations. The study comprised of 641 patients with sufficient data to analyze.Contrary to previous research, the findings of this study suggest that having RAS isoform mutations did not necessarily equate to a poor development of the disease. However, a pattern was found between the RAS isoform mutation seen and ones stage in life; HRAS isoform in infants, KRAS isoform in toddlers, and NRAS isoform in adolescence. This clinical study also found similar results as previous studies with the correlation of TP53 mutations and clinical outcome. TP53 mutations tended to result in a worsening development and clinical outcome of the disease. Although MYOD1 mutations make up a small percentage of ERMS, these mutations have been seen to have a negative prognosis and more studies should be conducted to understand how to treat the clinical condition of this specific mutation. Tumor Location
Tumor location plays an important role as RMS located in the parameningeal area, retroperitonium, pelvic, vulva, uterus, vagina, or trunk area genereally have poor prognosis. The anatomical position of parameningeal RMS makes it difficult to completely resect the entire tumor via surgery and may lead to tumor recurrence. Additionally, imaging that shows a tumor greater than 5 cm, presence of metastases, or positive lymph node status can indicate poor prognosis.