A New Way to Attack Early Metastatic Disease
There are bits of cancer that have spread, or metastasized, beyond the prostate, but not that many, and not at very many locations in the body. Cancer in this state is still vulnerable, and still responds to treatment.
In the blockbuster movie, Independence Day, terrifying space aliens invade earth. From one mother ship, dozens of equally deadly, smaller ships spread out around the planet. But these evil aliens are beaten by a tiny home force. The secret? They attack the mother ship, and without its protection, the smaller ships are vulnerable.
This is a pretty good model for what radiation oncologist Phuoc T. Tran, M.D., Ph.D., wants to do with metastatic prostate cancer in its earliest stages. He believes that by eliminating the bigger sites of cancer, tiny new ones won't be able to flourish. It's an idea that has shown success in the treatment of breast cancer, "where improved local control decreases metastatic as well as local relapse," Tran says. "This local treatment model is true for prostate cancer, too. Better control of localized cancer by adjuvant radiation to the area around the prostate (called the prostatic bed) lowers the risk of other metastases and improves overall survival. We believe that sites of macroscopic disease — visible on MRI or other images — support the maturation of microscopic spots of cancer into future metastases." Going after the cancer that can be seen "has substantial clinical implications" for the cancer too small to be seen, he adds. "This is hardly ever performed in prostate cancer."
In the spectrum of cancer, from localized to advanced metastatic disease, is a kind of midpoint called an oligometastatic state. There are bits of cancer that have spread, or metastasized, beyond the prostate, but not that many, and not at very many locations in the body. Cancer in this state is still vulnerable, and still responds to treatment. For example, "in patients with oligometastatic sarcomas or colorectal cancer, local radiation to the primary tumor combinedwith chemotherapy, can result in long term disease- free survival in between 25 and 40 percent of patients," says Tran. "Our own clinical experience suggests an oligometastatic state exists in a subset of prostate cancer patients who may benefit from local radiation treatment to all sites of macroscopic metastatic disease."
Picture, if you will, the bloodstream. It goes throughout the body, flowing in one direction. Cancer cells that make their way into the blood, like seeds floating on a river, leave the original tumor — the mother ship — and drift for a while, eventually coming to rest at a distant site, where they may start to grow. This is the generally accepted model of how cancer spreads. But Tran suspects that these circulating tumor cells (CTCs) get homesick — that they pay an occasional visit back to the original tumor, or maybe visit one of their siblings that has struck out on its own and built a home. These visits are invigorating: "The CTCs become more robust," he says, "and this cyclical process of CTCs interacting with more established cancer results in the release of signals that foster tumor growth." Like a domino effect, then, tumor growth leads to angiogenesis — the paving of new roads, made of blood vessels, to supply the tumor; angiogenesis is followed by immune evasion – the cancer mutates to dodge the body's militia of immune cells — and ultimately, "the formation of new, macroscopic metastases." This theory of macroscopic metastases being self-seeding communal sanctuaries is supported by recent genomic data from studies of human prostate cancer cells, Tran says.
What's the best way to target these little blots of cancer? Tran believes the key is stereotactic ablative radiation (SABR), "a highly focused, localized, high-dose radiation delivered in a hypofractionated course," meaning in several large doses, spread out over several days. "It's ideally suited for treatment of oligometastatic patients, and has shown high local control rates with minimal toxicity," he says. "SABR effectively targets the microenvironment of tumors, and in melanoma patients, has been shown to have antitumor effects on the irradiated tumor and an abscopal effect" — think of a shock wave, affecting areas not part of the original blast — "on distant metastases when combined with other immune system- stimulating agents."
Tran is starting a multi-institutional study aimed at killing oligometastatic cancer through SABR and immune system- targeting agents. This program is partly funded by an award from the National Cancer Institute to radiation oncologist Ted DeWeese and Director of Nuclear Medicine Martin Pomper, and by a Movember-Prostate Cancer Foundation Challenge award to Tran, who is the principal investigator, and to urologist Ashley Ross, DeWeese, Pomper, Adam Dicker (from Thomas Jefferson University), Max Diehn (from Stanford University), Charles Drake, Hao Wang, Kenneth Pienta and Mario Eisenberger. In 2015, among other honors and awards, Tran was appointed Clinical Director of Radiation Oncology and was named Associate Editor for the journal, Cancer Research.