Synergy with Metronomic Chemotherapy

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Anyone who has taken piano lessons should be familiar with the metronome—a device that clicks at regular intervals to form a steady beat.

Now, a growing body of research suggests a metronomic approach to chemotherapy dosing—with unremitted pulsing of medication—may improve outcomes for pancreatic cancer patients. The gist: Instead of high-dose, intermittent use of one or two chemotherapy drugs, oncologists are combining low doses of several agents with an uninterrupted regimen.

“With the low-dose approach, there’s less risk of toxicity so we’re able to deliver continuous therapy, which has the potential to be more effective and less toxic,” explains Azriel Hirschfeld, M.D., of Bruckner Oncology, The Bronx, New York.

The approach challenges the conventional wisdom of delivering chemotherapy drugs every few weeks at the highest possible doses—a toxic treatment schedule that not only leads to hair loss, vomiting, and extreme fatigue, but also cripples the body’s immune system, leaving patients vulnerable to new and recurring disease.

Metronomic chemotherapy, on the other hand, may offer more effective tumor control as well as fewer side effects. And it has a track record of patients surpassing their projected survival rates. This novel approach is rapidly changing the pancreatic cancer treatment landscape.

The Metronomic Concept

Conventional chemotherapy kills all rapidly dividing cells whether they’re healthy or not. While that approach may destroy the lion’s share of tumor cells, it often spares a number of tumor-initiating cells (TICs), which allows new, more aggressive tumors to grow and spread.

“When pancreatic cancer spreads, it becomes a systemic disease,” explains Allyson Ocean, M.D., medical oncologist at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York. “So you have to be able to give chemotherapy for longer periods of time and, since toxic side effects are cumulative, the only way to do that is by using lower doses.”

This metronomic approach inhibits the growth of TICs in the growing vascular network of the tumor. It hits cancer at the source while also suppressing the growth of resistant cells. And studies show it works. Researchers tested drugs at 50 percent, 25 percent, 12 percent and 6 percent of the approved maximum dose and discovered a fair amount of activity at 12 and 25 percent—and a diminishing dose-response with a lot of toxicity as it continued up the scale.

Another perk of the low-dose approach: Patients who are too weak or ill to tolerate standard chemotherapy regimens may be able to withstand a low-dose, continuous protocol. The most common side effects are mild nausea and fatigue. “So you’ve essentially created a more effective and less toxic treatment,” says Hirschfeld.

Taking Advantage of Synergy

Taking a steady, pulsed, metronomic approach to treatment not only minimizes toxicity (nausea, fatigue, and hair loss, for example), it also allows doctors to use multiple chemotherapy drugs simultaneously. In fact, laboratory studies show that using low doses of different drugs in tandem enhances their effectiveness. And because the regimen doesn’t derail the immune system (as high-dose chemotherapy does), it can continue to battle the cancer. But it’s not a novel concept.

“Dating back to the 1990s, I realized that if I gave a quarter of the dose, I would only produce a quarter of the toxicity so I could string more drugs together,” says Howard W. Bruckner, M.D., of Bruckner Oncology. “I paired drugs at lower concentration, and to my surprise, the drugs that didn’t work at all as a single agent showed significant activity. They were synergistic with the right partner.”

Because of the low toxicity, doctors are able to deliver drugs weekly or bi-weekly instead of every four weeks. So they’re pounding the tumor harder and more systematically but with fewer side effects. Inspired by these results, oncologists such as Ocean are launching clinical trials of metronomic chemotherapy to provide more hard data to support the use of low-dose combination chemotherapy as a first line of defense rather than a last resort.

“In the meantime, don’t be afraid to discuss these approaches with your doctor,” she says. “Choosing a low and slow dosing regimen may not only extend the life of a pancreatic cancer patient, it could also improve its quality.”

For more information on metronomic chemotherapy, read the article “Low-dose Continuous Chemotherapy as part of a New Combination of Drugs.”