MILAN – The combination of doxorubicin and ifosfamide is the best treatment for most patients with a sarcoma that does not have a proven targeted therapy, although a recent report from a large randomized study failed to prove that the combination surpassed doxorubicin alone for improving overall survival, said Dr. Robert S. Benjamin.

"From my point of view, this was clearly a positive study, but it was interpreted as a negative study" by the investigators who ran it, Dr. Benjamin said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

Among patients who received doxorubicin (Adriamycin) plus ifosfamide (Ifex), compared with those randomized to doxorubicin only, "the incidence of progressive disease was cut by more than half, the objective response rate was twice as high, and the time to progression was increased by more than 50%. Overall survival was also better" but did not reach statistical significance. "It was supposed to be 10% better for overall survival [based on the study’s design], but it was only 9% better and they considered that the same as zero," noted Dr. Benjamin, professor and chairman of sarcoma medical oncology at the University of Texas M.D. Anderson Cancer Center, Houston.

"Overall survival is a lousy endpoint," he said. "It measures everything that happens when you treat, but also everything that happens after" treatment is finished. Dr. Benjamin said his center was invited by the organizers of this phase III trial to participate, but he declined because the trial used overall survival as its primary endpoint.

The trial enrolled 455 patients with a locally-advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, aged 18-60 years at 38 centers in nine European countries and Canada. It included patients with more than 10 different sarcoma types including liposarcomas, synovial sarcomas, leiomyosarcomas, undifferentiated pleomorphic sarcomas, and unclassified high-grade sarcomas. The study randomized patients to either doxorubicin alone or intensified doxorubicin plus ifosfamide as first-line treatment. Patients were treated every 3 weeks for up to six cycles and were followed for a median of 56-59 months (Lancet Oncol. 2014 [doi:10.1016/S1470-2045(14)70063-4]).

The study’s primary endpoint, overall survival, averaged 12.8 months in the monotherapy arm and 14.3 months in the dual-agent arm, a hazard ratio of 0.83 that failed to meet statistical significance (P =.076), reported Dr. Ian Judson, professor and head of the sarcoma unit at the Royal Marsden Hospital in London, and his associates. However, median progression-free survival was 4.6 months in the doxorubicin-only arm and 7.4 months for the combined-treatment arm, a statistically significant difference (P = .003). Progressive disease occurred in 32% of the patients on monotherapy and in 13% of those on combined treatment.

The study’s authors concluded that if chemotherapy is used palliatively to relieve acute symptoms, then sequential treatment with single drugs would probably be less toxic without significantly impairing survival. For patients in whom symptoms could be relieved by tumor shrinkage, or if debulking of the tumor before surgery or radiotherapy is the goal, or if delaying disease progression as long as possible is the goal, then combination treatment is justified. They also cautioned against extrapolating the findings to patients older than 60 years, a limitation seconded by Dr. Benjamin. He cautioned against administering the combination to any patient older than 65 years or to patients with substantially impaired renal function.

But he disagreed with using doxorubicin as monotherapy unless tolerance was an issue. "Doxorubicin is a very good drug; it just shouldn’t be used by itself," he said.

Dr. Benjamin offered a few tips for using the doxorubicin and ifosfamide combination in practice: It’s important to use doxorubicin at the recommended dosage of 75 mg/m². If a patient cannot tolerate that dosage in combination with ifosfamide then the best option is to change to doxorubicin monotherapy to be sure the patient receives 75 mg/m². He recommended starting patients first on the doxorubicin and ifosfamide combination because it is the most toxic, with a less toxic pairing like gemcitabine (Gemzar) and docetaxel (Dosefirez) as second-line therapy because it’s harder for patients to switch to a more toxic regimen, he said. Dacarbazine also can pair effectively with doxorubicin. This combination is "almost as good as doxorubicin plus ifosfamide and is less toxic." He also noted the efficacy of trabectedin (Yondelis), which is available in European countries but not in the United States.

"These drugs all work, and the patient will need everything you have. You need to put it all together," Dr. Benjamin advised. "All the chemotherapy we currently have is grossly inadequate, but given what we have, use doxorubicin and ifosfamide for most patients with soft tissue sarcomas."

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Doxorubicin, ifosfamide combination touted for advanced sarcomas