Combining new and old drugs improves survival for soft-tissue cancer patients

Adding a novel monoclonal antibody therapy to traditional chemotherapy increased median survival by nearly a year in patients with advanced sarcoma, a lethal soft-tissue cancer. Findings from a multicenter clinical trial of the combination therapy, led by researchers at Columbia University Medical Center and NewYork-Presbyterian, represent the first appreciable improvement in sarcoma outcomes in decades.

We estimated from preclinical data that the new drug–olaratumab–might improve survival in these patients by a few months, but the extent of the improvement exceeded everybody’s expectations,” said study leader Gary K. Schwartz, MD, professor of medicine at Columbia University Medical Center and chief of the division of hematology and oncology at NewYork-Presbyterian/Columbia. “While sarcoma remains a fatal disease, we’re encouraged that we’re on the right track and hope to build on this progress.”

Soft-tissue sarcomas are a group of cancers that arise in fat, muscle, nerves, joint linings, blood vessels, and other tissues that connect, support, and surround various body structures. There are more than 50 different types of soft-tissue sarcomas.

If caught early, sarcomas can be treated effectively with surgery. However, if the disease spreads, or metastasizes, treatment with chemotherapy does relatively little to slow disease progression or improve survival. The median survival time after diagnosis of advanced disease is 12 to 16 months. In 2015, 12,000 people were diagnosed with soft-tissue sarcomas and 5,000 died of the disease, according to the American Cancer Society.

Several years ago, Dr. Schwartz (then at Memorial Sloan Kettering Cancer Center) reported that a cell-surface receptor called platelet-derived growth factor receptor alpha (PDGFR-alpha)–found in many people with soft-tissue sarcoma–appeared to play a key role in tumor growth in specific sub-types of soft-tissue sarcoma. By inhibiting this receptor, he was able to get the sarcoma cells to stop growing in his laboratory.

Working in close association with scientists at ImClone, since acquired by Eli Lilly and Company, he developed the clinical trial with the agent olaratumab, a human monoclonal antibody that blocks PDGFR-alpha and disrupts this signaling pathway, which is critical for sarcoma growth. The drug was also shown to enhance the effects of a standard chemotherapy called doxorubicin, which is routinely used in the treatment of sarcoma. The study was published in The Lancet.In

In a phase 2 clinical trial, 133 patients with metastatic soft-tissue sarcoma were given either doxorubicin or doxorubicin plus olaratumab. The median overall survival of patients in the doxorubicin group was 14.7 months, compared to 26.5 months in the doxorubicin-olaratumab group. Adding olaratumab to standard chemotherapy did not significantly increase treatment side effects.

As an oncologist, I am ecstatic that the drug worked as well as it did,” said Dr. Schwartz. “As a physician-scientist, however, I remain frustrated because we still don’t know exactly why it worked as well as it did. It might be directly affecting the tumor cells, the tumor microenvironment (cells immediately around the tumor cells), or even the immune cells. The future development of this drug will be helped by figuring this out.”

Dr. Schwartz and his colleagues are currently studying other potential drug targets for arresting the progression of soft-tissue sarcomas. “Sarcomas are complex. There are, in fact, multiple receptors on the cell surface. PDGFR-alpha is just one of the receptors that are overexpressed on sarcoma cells. We now have some ideas about how to combine drugs that block multiple types of these receptors, which will probably be more effective that targeting a single type of receptor,” he said.

Eli Lilly recently completed a larger, phase 3 clinical trial of olaratumab, which included some of Dr. Schwartz’s patients at Columbia/NewYork-Presbyterian. Results of the study have not yet been published. In the meantime, the FDA has granted the drug priority review as a potential treatment for advanced soft-tissue sarcoma.

Tap et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 2016;http://dx.doi.org/10.1016/S0140-6736(16)30587-6 [Abstract]

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Many skin cancer patients still too likely to sunburn

A recent study by researchers at Johns Hopkins concludes that a substantial number of people with a history of the most frequent kind of nonmelanoma skin cancers still get sunburned at the same rate as those without a previous history, probably because they are not using sun-protective methods the right way or in the right amounts.

The findings, which were based on self-reporting of sunburn and sun protection practices gathered from the National Health Interview Survey, urge skin doctors and other health care providers to better educate their patients about protective skin care practices, especially for those with a history of nonmelanoma skin cancer. The findings are published in the Journal of the American Academy of Dermatology.

It is important to look at how patients are currently practicing sun protection and what they are doing that is not very effective,” says Anna Chien, M.D., co-director of the Cutaneous Translational Research Program in the Department of Dermatology at the Johns Hopkins University School of Medicine. “Only then can we make strides in helping patients improve their sun protective practices by ensuring they do them the correct way.” Sun exposure is the leading cause of nonmelanoma skin cancers, and treatment is estimated to cost $4.8 billion in the U.S. annually.

In the United States, Chien says, approximately 13 million white non-Hispanic individuals have a history of at least one type of nonmelanoma skin cancer, including basal cell and squamous cell cancers, putting them at a well-documented higher risk for subsequent nonmelanoma skin cancer. For example, studies show that 40 percent of those with a history of basal cell carcinoma are diagnosed with another lesion within five years.

For the new study, investigators analyzed self-reported survey results about sun protective practices from 758 people with previous nonmelanoma skin cancer and from 34,161 people without a history of skin cancer. The study focused on non-Hispanic whites, the population most affected by nonmelanoma skin cancer. Of the people without history, 18,933 were female and 15,228 were male, and of those with history, 390 were female and 368 were male.

The researchers defined protective practices as using sunscreen when going outside on a sunny day for more than an hour, wearing long sleeves or a wide-brimmed hat, and staying in the shade when outside on a sunny day for more than one hour. They defined sun avoidance as not going out into the sun.
Overall, they concluded that 44.3 percent of people with nonmelanoma skin cancer history reported frequent use of shade, compared to 27 percent of people without a history of skin cancer, and 20.5 percent of those with a history of nonmelanoma skin cancer wore long sleeves, compared to 7.7 percent of those with no history.

Additionally, 26.1 percent of those with a history of nonmelanoma skin cancer said they wore a wide-brimmed hat when outside in the sun, compared to 10.5 percent of people without a history, and 53.7 percent of those with a history of nonmelanoma skin cancer said they wore sunscreen, compared to 33.1 percent of those without a history.

Moreover, 44.7 percent of those with a history of nonmelanoma skin cancer reported using more than one form of sun protection, while only 19.4 percent of those without a history of nonmelanoma skin cancer said they did so. Multimodality, the use of multiple skin-protective practices at a time, was associated with lower odds of sunburn. It also offers a highly beneficial approach to those with previous nonmelanoma skin cancer, says Chien.

Most importantly, the researchers say was the finding that although people with previous nonmelanoma skin cancer tend to use one or all of the protective practices, there was not a significant difference in reporting of sunburn compared to those without a history — 29.7 percent versus 40.7 percent. This means, Chien says, that although those with a history of skin cancer are proactively using protective methods, they may not be doing so effectively, especially among younger patients. Approximately two-thirds (66.9 percent) of individuals ages 18 to 39 reported sunburn.

Chien says that while sunscreen was the most common use of sun protection reported by participants, it was not associated with lower rates of sunburn in those with previous nonmelanoma skin cancer. While noting that self-reports, such as those on which the study is based, are not entirely reliable, the disconnect among those who use sunscreen and still get burned may occur because individuals are not applying sunscreen effectively. Explaining the correct ways — such as how much and how often — to apply sunscreen to patients is key, says Chien.

These results suggest that physicians need to go the extra step in educating patients on the most optimal way of utilizing sun protection methods. Public health messages should also emphasize not only sun protection but how to do it correctly,” Chien says.

The researchers caution that although the data were pulled from a national survey, the results are self-reported and therefore may have some bias. In addition, Chien says, nonmelanoma skin cancer tends to be considered less important than melanoma and is thus under-reported.

The bottom line is that people should be using multiple forms of skin protective practices,” says Chien. “That means incorporating shade or sun avoidance into a daily routine, or wearing a wide-brimmed hat while also applying sunscreen correctly.”

Fischer et al. Sunburn and sun-protective behaviors among adults with and without previous nonmelanoma skin cancer (NMSC): A population-based study. J. Am. Acad. Dermatol. 2016;75:371–379 [Abstract]