A large trial comparing single and combination chemotherapy in the first-line treatment of soft tissue sarcoma failed to meet its primary overall survival end point. However, the results were of borderline significance, and secondary end points favored the combination, so was the trial really negative?
This was the question raised here at the 2012 European Society for Medical Oncology Congress by one commentator.
Speaking at a Best of ESMO summary session, Alessandro Gronchi, MD, a surgical oncologist from the Instituto Nazionale Tumori in Milan, Italy, suggested that the results can be interpreted as providing evidence for both treatment options.
In the palliative setting, single-agent chemotherapy with doxorubicin should be used, he said. However, if there is a chance of cure or if a reduction of tumor size is needed to improve symptoms and quality of life, then the combination of doxorubicin plus ifosfamide should be used, he said.
Although there have been several previous trials comparing single and combination chemotherapy, none have given a definitive answer, he noted.
There has been a lot of transatlantic and transcultural debate about which is the best first-line option, explained study author Winette van der Graaf, MD, from Radboud University Medical Center in Nijmegen, the Netherlands. This is the reason her team conducted this large randomized phase 3 study.
The trial, conducted by the European Organization for Research and Treatment of Cancer (EORTC), involved 455 patients recruited from 9 countries. Patients had grade 2 or 3 advanced or metastatic soft tissue sarcoma, and were 18 to 60 years of age.
Both of these factors are notable, said George Demetri, MD, from the Dana-Farber Cancer Center in Boston, Massachusetts, who was not involved with the study. He noted that sarcoma is disproportionately common in children, and in adults sarcoma is more common in the elderly. He explained that all sarcomas are of mesenchymal origin but that they cover a very broad range of different histologic subtypes.
Single vs Combo Chemotherapy
Patients were randomized to receive doxorubicin (75 mg/m² as a bolus or 72-hour infusion) either alone or in combination with ifosfamide (10 g/m² over 4 days with the colony-stimulating factor pegfilgrastim), and were treated every 3 weeks until disease progression or the completion of 6 cycles of therapy.
After a median follow-up of 56 months, there was no significant difference in median overall survival, the primary end point, between the combination and single-agent groups (14.3 vs 12.8; hazard ratio [HR], 0.83; P = .0076).
Secondary end points were significantly better with the combination. Median progression-free survival was 7.4 months with the combination and 4.6 months with the single agent (HR, 0.74; P = .003). Most of this effect was seen in patients 40 to 50 years of age, Dr. van der Graaf noted. In addition, the overall response rate with the combination was double that with doxorubicin alone (26.5% vs 13.6%).
However, the combination was "considerably more toxic," Dr. van der Graaf said. Grade 3 or higher adverse events reported in the combination and single-agent groups included febrile neutropenia (45.9% vs 13.5%), leucopenia (43.3% vs 17.9%), anemia (34.9% vs 19.7%), and thrombocytopenia (33.5% vs 0.4%).
The lack of significant survival results means that single-agent doxorubicin remains the standard treatment for first-line use, Dr. van der Graaf concluded.
However, she noted that "if surgery for unresectable tumors or (curative) metastasectomy is foreseen, combination therapy can be considered."
"In highly symptomatic disease in patients without comorbidity, combination treatment is optional. The pros and cons should, as always, be discussed with the patients," she said, adding that "this is easier now that we have the results of this study."
Poor Prognosis
Dr. Demetri reminded the audience that metastatic soft tissue sarcomas have variable clinical behaviors, but they are nearly all incurable. "Therefore, our intention is to palliate and prolong life with the highest possible quality," he explained.
The median survival for these patients is about 1 year, he said. In this study, after 1 year, 60% of patients in the combination group were still alive, compared with 51% in the single-agent group. During the first year of the study, there was some divergence between the 2 curves, he noted; disease control was longer with the combination than with doxorubicin alone (7.4 vs 5.0 months). For a patient who may have only 1 year to live, there is a chance that more of that time will be disease-free when treated with the combination, he said.
Dr. Demetri concluded that, in his opinion, if a patient is asymptomatic, the best first-line therapy remains single-agent doxorubicin. However, if a patient is symptomatic or if tumor shrinkage is required because the tumor is causing pain, then he would suggest using the combination of doxorubicin plus ifosfamide.
But there is another option, he reminded the audience; the targeted agent pazopanib (Votrient) was approved for use in sarcoma in April in the United States and in August in Europe.
"This is an important step," Dr. Demetri explained in a previous interview, because it offers an alternative to chemotherapy. Pazopanib is an oral drug with a milder adverse-effect profile, and might be preferable for patients who have small asymptomatic tumors, he said.
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