GeDDiS: insight into frontline therapy in soft tissue sarcoma
Authors: William D Tap
Journal: The Lancet Oncology (2017)

Gemcitabine has known activity in sarcoma; although its exact role, indication, or best combination is still debated. The combination of gemcitabine and docetaxel gained favour in the USA after efficacy was noted in uterine leiomyosarcoma1Hensley ML Maki R Venkatraman E et al.Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial.J Clin Oncol. 2002; 20: 2824-2831Crossref PubMed Scopus (575) Google Scholar, 2Hensley ML Blessing JA Mannel R Rose PG Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study.Gynecol Oncol. 2008; 109: 323-328Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar and later in sarcoma, generally with superiority over gemcitabine alone.3Maki RG Wathen JK Patel SR et al.Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].J Clin Oncol. 2007; 25: 2755-2763Crossref PubMed Scopus (568) Google Scholar However, this combination is used to a lesser extent in Europe, partly due to more equivocal data in leiomyosarcoma,4Pautier P Floquet A Penel N et al.Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study).Oncologist. 2012; 17: 1213-1220Crossref PubMed Scopus (160) Google Scholar noted efficacy of other gemcitabine-based regimens,5Garcia-Del-Muro X López-Pousa A Maurel J et al.Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study.J Clin Oncol. 2011; 29: 2528-2533Crossref PubMed Scopus (198) Google Scholar and potential issues of access as described in the GeDDiS6Seddon B Strauss SJ Whelan J et al.Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.Lancet Oncol. 2017; (published online Sept 4.)http://dx.doi.org/10.1016/S1470-2045(17)30622-8PubMed Google Scholar trial in The Lancet Oncology.6Seddon B Strauss SJ Whelan J et al.Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.Lancet Oncol. 2017; (published online Sept 4.)http://dx.doi.org/10.1016/S1470-2045(17)30622-8PubMed Google Scholar Recently, several phase 3 studies have provided substantial insight into the use of anthracyclines and alkylators as first-line treatments for patients with advanced sarcoma.7Judson I Verweij J Gelderblom H et al.Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial.Lancet Oncol. 2014; 15: 415-423Summary Full Text Full Text PDF PubMed Scopus (693) Google Scholar, 8Ryan CW Merimsky O Agulnik M et al.PICASSO III: A phase III, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma.J Clin Oncol. 2016; (published online Sep 12.)DOI: 10.1200/JCO.2016.67.6684Crossref Scopus (128) Google Scholar, 9Tap WD Papai Z Van Tine BA et al.Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2017; 18: 1089-1103Summary Full Text Full Text PDF PubMed Scopus (163) Google Scholar The GeDDiS6Seddon B Strauss SJ Whelan J et al.Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.Lancet Oncol. 2017; (published online Sept 4.)http://dx.doi.org/10.1016/S1470-2045(17)30622-8PubMed Google Scholar trial iis the first to shed comparative light on the efficacy of gemcitabine and docetaxel versus doxorubicin alone in this setting. The primary endpoint of the trial—progression-free survival at 24 weeks—did not differ between the two treatment groups (46·3% [95% CI 37·5–54·6] in the doxorubicin group vs 46·4% [37·5–54·8] in the gemcitabine and docetaxel group). The GeDDiS trial investigators concluded that the combination should not be recommended as routine, while doxorubicin should remain standard of care, in the first-line setting for patients with advanced soft-tissue sarcoma. The latter part of GeDDiS' conclusion that doxorubicin should remain routine, with a slight change in modifiers, is a logical one. Most clinicians agree that doxorubicin is a (but not necessarily the only) standard first-line therapy for patients with advanced sarcoma. However, the former part of the conclusion, that the combination should not be recommended as routine, is more debatable. The results of the GeDDiS trial should allow individual clinicians to determine how to position and in what clinical context to use gemcitabine and docetaxel for the care of their patients. The main confounder in the trial is the starting dose and overall usage pattern of the combination. In conventional practice, gemcitabine and docetaxel is routinely administered with gemcitabine 900 mg/m2 given at a 10 mg/m2 per min infusion rate on days 1 and 8 and docetaxel 75 mg/m2 on day 8 of a 21-day cycle. The docetaxel dose is lower than the 100 mg/m2 used in early trials to help mitigate toxicity.1Hensley ML Maki R Venkatraman E et al.Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial.J Clin Oncol. 2002; 20: 2824-2831Crossref PubMed Scopus (575) Google Scholar, 2Hensley ML Blessing JA Mannel R Rose PG Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study.Gynecol Oncol. 2008; 109: 323-328Summary Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 3Maki RG Wathen JK Patel SR et al.Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].J Clin Oncol. 2007; 25: 2755-2763Crossref PubMed Scopus (568) Google Scholar The regimen is generally considered well tolerated with predictable and manageable toxicity. In the GeDDiS trial, patients received gemcitabine 675 mg/m2 at a 7·5 mg/m2 per min infusion rate on days 1 and 8 and docetaxel 75 mg/m2 on day 8 of a 21-day cycle. The regimen was capped at six cycles. The dose, infusion rate, and number of cycles of gemcitabine is relevant to the results and calls into question how the combination was perceived in trial design and used by investigators. Of the combination, gemcitabine is thought to be the more active agent in sarcoma. The overall lack of grade 3 or 4 thrombocytopenia (0%) in the combination group, at least compared with previous studies,3Maki RG Wathen JK Patel SR et al.Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].J Clin Oncol. 2007; 25: 2755-2763Crossref PubMed Scopus (568) Google Scholar, 4Pautier P Floquet A Penel N et al.Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study).Oncologist. 2012; 17: 1213-1220Crossref PubMed Scopus (160) Google Scholar suggests that gemcitabine might have been underdosed and underused in GeDDiS. Additionally, the combination can often be given for many cycles beyond just six. The dose reduction of the gemcitabine and the fact that the study limited the number of cycles could have biased the design against the combination group. The proportion of patients who received the full treatment regimen (ie, all six cycles) of gemcitabine and docetaxel (39% vs 56% doxorubicin) is also of interest, even with its lower starting dose, the need for fewer dose reductions (18% gemcitabine and docetaxel vs 27% doxorubicin), a significantly lower incidence of cytopenias, and a similar grade 3–4 adverse event profile. Finally, it is curious that more patients in the combination group went on to receive doxorubicin as a second-line therapy after disease progression, whereas very few patients in the doxorubicin group went on to receive the combination (42% vs 13%). Are these all signs of a preconceived investigator bias in this open-label study? Does the fact that the combination performed as well as it did under these circumstances suggest that it does have activity as a first-line treatment? Considering that no statistically significant benefit was noted in the proportion of patients achieving an objective response (19% doxorubicin vs 20% gemcitabine and docetaxel), progression-free survival (hazard ratio [HR] 1·28, 95% CI 0·99–1·65, p=0·06), and overall survival (HR 1·14, 95% CI 0·83–1·57, p=0·41), one could prudently conclude that neither regimen is superior. This concept would allow clinicians to choose the regimen they feel is most appropriate for the patient based on their clinical scenario, comorbidities, performance status, and sarcoma subtype. Choosing a first-line regimen based on sarcoma subtype is of particular importance for the patient. GeDDiS does provide guidance in this regard. Comparison of all leiomyosarcomas and uterine leiomyosarcoma to other sarcoma subtypes showed no difference in outcomes between the two treatment groups. This finding shows that that the inclusion of patients with leiomyosarcoma (46% of patients) did not drive the data in a specific direction. It also argues for equipoise in consideration for either doxorubicin or gemcitabine and docetaxel as a first-line treatment for patients with soft-tissue sarcomas including leiomyosarcoma. The authors should be congratulated for not only publishing the results of this trial with such transparency and completeness, but also for having the foresight to design and the ability to perform and complete this very important trial. Even though the outcome of the trial was negative based on pre-study statistical assumptions, the results should guide many clinicians as they practice medicine and hopefully make gemcitabine and docetaxel more widely available to patients in countries that still have issues of access. I have received personal fees from Eli Lilly, EMD Serono, Novartis, Eisai, Janssen, Immune Design, Adaptimmune, Ariad, Daiichi Sankyo, Plexxikon, Morphotek, Advaxis, and Tracon, outside of the submitted work. Additionally, I have a patent using ATRX as a companion diagnostic for CDK4 inhibitors pending, and a patent for methods for drug discovery pending. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trialDoxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. Full-Text PDF Open Access