First-line Doxorubicin for Advanced Sarcoma, Not Combo?

Alexander M. Castellino, PhD

September 27, 2017

Doxorubicin should remain first-line therapy for patients with soft-tissue sarcoma, conclude trialists who compared it with the combination of gemcitabine and docetaxel. They make this statement despite the fact that the trial, known as GeDDis, found that progression-free survival (PFS) and overall survival (OS) were similar for the two treatments.

"[Although our data] support a conclusion that either schedule can be used according to patient or clinician preference, our results indicate the need for caution with such an approach given the greater difficulty in delivery and toxicity of gemcitabine and docetaxel, and indeed the higher cost of this combination regimen," the GeDDiS investigators write.

Further, they conclude that "doxorubicin should remain standard of care as first-line treatment for most patients with advanced soft-tissue sarcoma, and that there is no subgroup of patients for whom gemcitabine and docetaxel should be routinely recommended."

Beatrice Seddon, MD, of the University College London Hospitals National Health Service Foundation Trust, United Kingdom, was the corresponding author of GeDDiS, which was published online September 4 in the Lancet Oncology.

In an accompanying commentary, William D. Tap, MD, of the Memorial Sloan Kettering Cancer Center, New York City, agrees that doxorubicin is a standard first-line therapy for patients with advanced sarcoma. However, he parts company with the trialists on their comments about the combination of gemcitabine plus docetaxel: "that the combination should not be recommended as routine is more debatable," he notes.

Dr Tap indicates in his commentary that the combination of gemcitabine and docetaxel is still a viable option in the front-line setting. "[GeDDiS] argues for equipoise in consideration for either doxorubicin or gemcitabine and docetaxel as a first-line treatment for patients with soft-tissue sarcomas including leiomyosarcomas," he observes.

The GeDDiS Study

GeDDiS was a multicenter, randomized, phase 3 study that recruited patients with previously treated high-grade advanced soft-tissue sarcomas (Trojani grade 2 or 3). The patients, who had measurable disease as determined in accordance with Response Evaluation Criteria in Solid Tumors (RESIST), had undergone treatment in the United Kingdom and Switzerland. They were randomly allocated to receive either doxorubicin (n = 129) or the combination of gemcitabine and docetaxel (n = 128).

The GeDDiS investigators note that the combination has seen increasing use in both leiomyosarcoma and locally advanced or metastatic soft-tissue sarcoma. "Robust evidence is needed to establish the roles of gemcitabine and docetaxel and doxorubicin as first-line treatments for this disease," they note.

Doxorubicin was given at an intravenous dose of 75 mg/m2 on day 1 every 3 weeks.

Gemcitabine was provided intravenously at a dose on 675 mg/m2 on day 1 and again on day 8 along with docetaxel 75 mg/m2; the combination was also given every 3 weeks.

Patients received six cycles of treatment in the absence of disease progression or intolerable side effects.

Results Similar in Both Arms

The patients in the study had 22 different histologic subtypes; 46% had leiomyosarcomas. The GeDDiS investigators indicate that this population is representative of the general population with advanced soft-tissue sarcoma.

The survival results were similar in both arms of the trial. There was no difference in PFS at 2 weeks between the two groups ― 46.3% for the doxorubicin group, and 46.4% for the gemcitabine combination group. Median PFS for the two groups was 23.3 and 23.7 weeks, respectively.

OS followed a similar trend. OS at 2 weeks was 86.8% for the doxorubicin group, and 82.6% for the gemcitabine combination group. Median OS for the two groups was 76.3 and 67.3 weeks, respectively.

Objective response rates were also similar ― 19% for the doxorubicin group, and 20% for the gemcitabine combination group.

The most common grade 3/4 adverse events (doxorubicin vs gemcitabine combination) were neutropenia (25% vs 20%), febrile neutropenia (20% vs 12%), fatigue (6% vs 14%), oral mucositis (14% vs 2%), and pain (8% vs 10%).

Combination Dosing and Pattern of Use Are Confounders

Dr Tap suggests that this study may have used too low a dose of gemcitabine. He notes that gemcitabine is typically used at a dose of 900 mg/m2 at 10 mg/m2 per min and docetaxel at 75 mg/m 2. Gemcitabine was given at a lower dose and at an infusion rate of 7.5 mg/m2 in the GeDDiS trial, and the number of cycles was capped at six.

"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 the investigators," Dr Tap comments. He notes that the combination can be given for many cycles beyond six. The reduced dose of gemcitabine and the limited cycles of the combination could have biased the design against the combination group, Dr Tap suggests.

Although gemcitabine was provided at a lower dose and there were fewer toxicities and fewer dose reductions with the gemcitabine combination, fewer patients completed the six cycles of combination therapy ― 39% vs 56% for doxorubicin. In addition, only 13% of patients who experienced disease progression with doxorubicin went on to receive the gemcitabine combination, whereas 42% of patients who experienced disease progression with the combination received doxorubicin.

Dr Tap comments that these findings pose several questions. "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 in the first-line setting?" he asks.

Dr Tap argues that with no significant benefit noted, "one could prudently conclude that neither regimen is superior.

One could prudently conclude that neither regimen is superior. Dr William Tap

"This concept could 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," he adds.

The GeDDiS investigators note that their decision to use the reduced gemcitabine dose was based on prior studies, which showed higher toxicity with the normal dose when used long term. "We therefore made a pragmatic decision to dose modify the schedule to make it more suitable for patients receiving palliative chemotherapy," they write. Concerning the fact that fewer patients experienced disease progression with doxorubicin than with the gemcitabine combination, the study investigators write: "This difference is because for many UK hospitals at the time of the GeDDiS trial, the combination of gemcitabine and docetaxel was not funded and therefore unavailable to clinicians."

Dr Tap hopes this situation may change. "The results [of GeDDiS] 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," he writes.

The investigators concede investigator bias with respet to the fact that fewer patients who received the gemcitabine combination completed six cycles of therapy. "The excess of patients stopping gemcitabine and docetaxel early might also reflect a bias in clinicians to stop treatment earlier in the experimental group, in the knowledge that patients could go on to receive standard doxorubicin-based treatment," they write. The doses of the combination that were missed or delayed might represent undertreatment in the group, they note.

Regardless of investigator bias, the GeDDiS investigators note that the combination of gemcitabine and docetaxel requires an additional hospital visit in each cycle and that the infusion takes longer to administer. These factors place an "added burden on patients with incurable disease receiving palliative chemotherapy."

"There are economic, as well as personal, disadvantages to gemcitabine and docetaxel because it is a more expensive treatment regimen than doxorubicin because of higher drug costs, more frequent and longer hospital visits are needed for treatment, and increased requirements for supportive medications," the GeDDiS investigators note.

His own reservations aside, Dr Tap applauds the publication of GeDDiS. "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," he commented.

The GeDDiS investigators call for randomized trials to evaluate emerging treatments in comparison with standard ones. "The study also highlights the importance of doing randomised trials in rare cancers to rigorously compare new treatments with established standard treatments, rather than extrapolating promising results from smaller non-comparative trials," they conclude.

The GeDDiS study was developed through and funded by the UK National Cancer Research Institute Sarcoma Clinical Studies Group. Several authors of the GeDDiS study have disclosed relationships with industry, as described in the original article. Dr Tap has 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. He also has a patent pending for the use of ATRX as a companion diagnostic method for CDK4 inhibitors.

Lancet Oncol. Published online September 4, 2017. Full text, Commentary

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