WHICH CHEMOTHERAPY FOR WHAT SARCOMAS?

If there's one thing that all sarcoma experts can agree on, it's the fact that no two sarcoma experts seem to completely agree on the relative benefits and risks of using neoadjuvant or adjuvant chemotherapy in adults with soft-tissue sarcomas.

The confusion is partly due to this hard truth: high-quality, authoritative data are hard to come by in sarcoma.

"There have been at least 22 randomized clinical trials looking to see if neoadjuvant or adjuvant chemotherapy has any impact on cure rates in patients with resectable sarcomas, and despite 22 studies, the jury is still out," said Edwin Choy, MD, PhD, a medical oncologist at the Center for Sarcoma and Connective Tissue Oncology at the Massachusetts General Hospital Cancer Center in Boston.

"So four or five of those studies are positive, meaning they say 'yes, we should do it", four or five studies are negative, meaning that people who got the chemotherapy actually did worse — had a lower cure rate than people who didn't get any chemotherapy — and then the other 12 or so studies are largely inconclusive," he said in an interview with Medscape Medical News.

Lee J. Helman, MD, head of the molecular oncology section of the pediatric oncology branch at the National Cancer Institute's Center for Cancer Research in Bethesda, Maryland, agreed, noting that when investigators attempt to answer this question by conducting systematic reviews and meta-analyses, "you get three studies that are positive, and three studies that are negative."

Large clinical trials with potentially authoritative results are difficult to conduct because of sarcomas' rarity, which means that studies are typically small and underpowered, Dr Choy said.

Dr Helman, however, is quick to point out that for pediatric patients with the more common sarcomas — Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma — the benefits of neoadjuvant chemotherapy are unequivocal.

The consensus is that [these] pediatric sarcomas absolutely benefit from neoadjuvant chemotherapy, and almost all patients get neoadjuvant chemotherapy," he said in an interview with Medscape Medical News.

Still, some pediatric sarcomas are like adult sarcomas.

"When you get to pediatric sarcomas that are more like adult soft tissue sarcomas, however, they tend to be less chemosensitive. The problem is that many, many studies test a drug in [adult] 'soft-tissue sarcomas,' and soft-tissue sarcomas are many, many histologies," he said.

Studies of two drugs recently approved by the US Food and Drug Administration for use in adults with sarcoma — trabectedin (Yondelis, Janssen Oncology) and pazopanib (Votrient, Novartis) — excluded patients with certain sarcomas that were unlikely to be responsive to the drugs, but still included patients with a number of different sarcoma histologies to have enough patients to detect a treatment difference, Dr Helman noted.

For most sarcomas, the best treatment is complete resection with adequate surgical margins. Where there appears to be consensus that chemotherapy may be beneficial is in patients with tumors larger than 5 cm, deeply seated tumors, and those with high-grade histology, he said.

In addition to surgery and radiation, Dr Choy and colleagues tend to favor multidrug neoadjuvant chemotherapy and radiation for high-risk sarcomas with histologies that are sensitive to chemotherapy, such as synovial sarcoma and myxoid liposarcoma.

In contrast, myxofibrosarcomas and chondrosarcomas tend to be insensitive to chemotherapy, and patients with these types of sarcoma would be unlikely to benefit. The decision is also based on the presence of high-risk features, including tumor size, depth, grade, and patient age.

In general, Dr Helman recommends chemotherapy for younger, fitter patients who are able to withstand the rigors of cytotoxic chemotherapy and have high-risk tumors.

In his discussion of the relative risks and benefits, he tells adult patients that the data supporting the recommendation are "not compelling" because of the lack of randomized trial data.

Dr Helman would also say, when fitting, that "I believe that these tumors are likely to be sensitive to chemotherapy, and I believe our best shot is to treat it at our first go round."

PET Theory

Although the evidence is spotty, there are data that appear to support the use of neoadjuvant chemotherapy in adult sarcomas.

As reported by Medscape Medical News, a study published in 2005 and a recent meta-analysis showed that in patients with soft-tissue sarcomas of the extremities, ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) could provide useful prognostic information based on maximum standardized uptake values (SUVmax) of ¹⁸F-FDG.

In the 2005 study, both SUVmax before neoadjuvant chemotherapy and change in SUVmax after chemotherapy independently identified patients at high risk for tumor recurrence.

A coauthor of that study, Janet F. Eary, MD, professor of radiology and director of the Advanced Imaging Facility at the University of Alabama School of Medicine in Birmingham, told Medscape Medical News that "when we validated that data, what it showed was that in the population we looked after, chemotherapy — neoadjuvant chemotherapy — actually had an effect."

Dr Eary said that she and her colleagues have supported the benefits of neoadjuvant chemotherapy in soft-tissue sarcomas since the late 1990s, and that "we've never understood" why it is not used more consistently in either the United States or Canada.

The Problem With Study Data on a Rare Cancer

The experts interviewed by Medscape Medical News further explained how and why the data on chemotherapy and sarcomas are murky.

Soft-tissue sarcomas account for less than 1% of all cancers diagnosed in the United States, with an estimated 12,000 new cases annually. The relative rarity of sarcomas makes it difficult for investigators to recruit enough patients for adequately powered clinical trials, and as a result, for every study suggesting a benefit for chemotherapy, there is an equal and opposite study showing equivocal benefit at best

While it's common to do adjuvant or neoadjuvant chemotherapy studies in 2000 patients with lung cancer, for example, "you can imagine how hard it's going to be to do a 2000-patient study in sarcoma. And so, if you only do a 300-patient study, then that study would only be positive if statistically the size of the effect was huge," Dr Choy explained.

The efficacy of chemotherapy in sarcoma in general is probably relatively modest, he said.

"It's not the case that everyone who doesn't get chemotherapy will die of their disease quickly, and everyone who gets chemotherapy will be cured forever. If that were the case, then we could find it out with a 10-patient study," he said.

Another problem with clinical trials is that to accrue sufficient patients for adequately powered studies, investigators have often lumped together sarcomas with different histologies with differing degrees of responsiveness to chemotherapy, Dr Choy said, echoing Dr Helman's comments.