The Future of Carbon Therapy
American-made technology is ideal for treating multiple or treatment-resistant tumors but no U.S. medical center offers it—something the National Cancer Institute has vowed to change.
Source: Heidelberg Ion-Beam Therapy Center/Heidelberg University Hospital. Reprinted with permission.
It has all the trappings of a homegrown success, carbon therapy. It was born here—developed in government-funded laboratories in California. Its high-tech technologies are massive in scale—powered by nothing less than a huge particle accelerator. And in the crowded commercial lot of modern medical treatments, carbon therapy is something of the Cadillac—a capital-intensive modality, but one that's ideal for treating certain complex, hard-to-treat or multitudinous tumors. Some would call it a wondrous treatment, enabling otherwise untreatable cancers to be cured.
Carbon ion therapy is truly American in any number of ways except perhaps one: Nowhere in the United States can you find it.
"We invented this technology and yet we still don’t even have it on our grounds," said biologist Eleanor Blakely, who was a staff scientist under Cornelius Tobias at Lawrence Berkeley National Laboratory, where this technology was developed, in the 1970s. She authored or co-authored some of the first papers on the effects of high-energy, heavy-ion beams on cell survival, which also occurred at a unique time of clinical trials in the United States. "It is really disturbing scientifically that we cannot offer it to our population in the United States."
But Blakely said she is reassured by the fact that the National Cancer Institute, a component of the National Institutes of Health, now has a confirmed goal to make a carbon therapy instrument and treatment center in this country.
"With all the people putting attention to it, we will have something happen real soon," Blakely said.
From the Frontier to the Forefront of Cancer Treatment
Experts agree that carbon ion therapy holds great promise for cancer treatment because of the fundamental biology and physics at play. A carbon ion can deliver higher amounts of energy to a tumor than an X-ray or proton beam. Sent out on a beam, its ions strike tumors with a clustering effect that can overwhelm the tumor’s ability to persist or grow, especially damaging cancer cells at the DNA level. Researchers also say that carbon ion treatment causes less damage to healthy tissue near the tumor because the ionic beam minimally disperses its energy before and after hitting its tumor target.
Some would say the age of carbon therapy is here. In fact, in Germany and Japan especially, there are new ideas being examined with some already tested and results published in the medical literature that is read in the United States. These include combining the carbon ion therapy with chemotherapy and immunotherapy, linking it with X-ray radiation therapy or proton therapy or combining it with helium ions or heavy ions, such as oxygen.
But in the United States, many public health issues become mired in contention, and carbon ion therapy is no exception. While the United States does not have a single carbon ion therapy center, Japan leads the way with five centers built, and there are active carbon ion therapy facilities in Germany, Italy, China and Austria. Thousands of people have been treated to date. One treatment team alone, led by Hirohiko Tsujii of Japan, has given some 10,000 patients carbon ion therapy.
In the United States part of the dilemma begins with costs: Offering carbon ion therapy requires building a special center that would likely cost more than 100 million dollars. Funding for research efforts competes for resources with other initiatives. Furthermore, carbon ion therapy is associated, rightly or wrongly, with the experience of proton therapy, which has a history of cost challenges, a long learning period, and the particular challenge of advancing a new health technology with necessary but ethical testing. This is important in the United States because major medical centers with new technology need approval from the Food and Drug Administration, and treatments have to satisfy the U.S. norm of Phase 3 random blind trials.
Proponents of carbon ion therapy are nonetheless determined to build at least one or two centers in the United States. The biggest boost came in 2013 when National Institutes of Health’s National Cancer Institute (NCI) issued a Planning for a National Center for Particle Beam Radiation Therapy Research (P20) fund for treatment and research centers. The P20 specifies that the proposed centers will use proton and heavier ion beams “including but not necessarily limited to carbon beams.” A team at the University of Texas Southwestern Medical Center (UT Southwestern), for example, has already completed their planning project.
The carbon ion proponents are encouraged for other reasons, too. There are international collaborations for testing carbon ion, including one recently set up in Shanghai in which the Montefiore Einstein Center for Cancer Care in New York participates. Additionally, the last several years have seen the publication of good results from carbon ion therapy centers overseas, which bolsters the U.S. efforts to build a treatment center here.
The Fundamental Biology and Physics
Successful imaging of the tumor margins as well as a robust estimation of the dosage needed to kill the cancerous cells therein are critical to carbon therapy, as they are with any type of treatment. But the unique therapeutic strength of carbon ion beams, and other heavy ions considered for cancer therapy, emerge from the underlying physics -- specifically the treatment's characteristic Bragg curve and Bragg peak.
The Bragg peak is the point at which the ions deposit the bulk of their energy, and the Bragg curve is a measure of the energy dissipated as the ions travel through surrounding tissue to reach the tumor. Carbon therapy has a single peak, with a sharp drop in energy after the peak, and a long front tail, which allows the ions to enter the body, reach a tumor and deposit a huge payload of bulk energy to that target without damaging surrounding tissue.
Physicist Derek Lowensteen, recently retired from Brookhaven National Laboratory, supervised supervised ion beams at Brookhaven’s NASA Space Radiation Laboratory (NSPL), where space mission health impacts are studied.
The physics are such that as you go up in mass, you get more energy—but only at a trade-off. As ions grow heavier, the distribution of energy also changes, Lowensteen explained.
"You can get more energy deposited into the tumor cell. On the other hand, its Bragg Peak is very broad,” said Lowensteen. "The beam will stop, but it has a long tail, and that long tail provides a dose to the patient in an area you don’t want it to be deposited."
The biology effectiveness of ion therapy is characterized by what is known as linear energy transfer, which is a metric of deposited energy within the tumor margins. Massachusetts General Hospital radiobiologist Kathryn Held, who has recently studied the effect of ions on lung cancer cells at the NASA Space Radiation Laboratory at Brookhaven, explained, "There is a concentration or clustering of DNA damage in cells irradiated with heavier charged particles. And because this is a concentration of many damages close to each other on the DNA structure, it is much more difficult for the cellular enzymatic process to accurately, if at all, repair that damage."
But it's not all about energy. Held pointed out that another key biological factor is that tumor cells, at least their central parts, are often hypoxic, or low in oxygen concentration. The tumor blocks oxygen-carrying blood vessels. "When cells have low oxygen concentration they are more resistant to conventional photon, X-ray and gamma ray radiation," Held said.
Lawrence Berkeley's Blakely has studied ion beams and their biological effects since the 1970s (see side bar), and she highlighted that the effective linear energy transfer is correlated with significantly reduced oxygen enhancement ratio. The oxygen enhancement ratio signifies the proportion of oxic and hypoxic cells, with hypoxic tumor cells being resistant to conventional radiotherapies. The reduced oxygen enhancement ratio indicates that these radioresistant cells are increasing effectively killed.
So when you weigh all the different scientific parameters important for an ion treatment—Bragg Peak, linear energy transfer and oxygen enhancement ratio—they may not coincide with the same ion. However, Blakely’s influential early research and current clinical successes do indicate that carbon is one ion where the physics and biology work very well together.
“It has the sweet spot,” said UT Southwestern cancer researcher Michael Story about the carbon ion.
From the Coast of Japan to the Plains of Texas
American doctors look around the world and see successes, especially in Japan and Germany. Some cancers that are very resistant to radiotherapies, and the tumor cells repair quickly. These cancers are prime focuses of carbon ion therapy. In Japan, Hirohito Tsujii, who has close ties with many U.S. researchers, has led carbon ion therapy for many years, treating around 10,000 people with carbon ion therapy at Japan’s National Institute of Radiological Sciences in Chiba, Japan.
Photo courtesy of Hirohiko Tsujji
Tsujii has treated prostate cancer, lung cancer, pancreatic cancer, liver cancer, post-operative occurrence of rectal cancer and other forms of cancers. Tsujii has also treated inoperable pancreatic cancer with carbon ions, and he said 50 percent of these patients survive for two years, which is double the survival rate seen for other treatments. Tsujii concentrates on hypo-fractioned doses, which are less frequent but stronger and more precise treatments. He pointed out that early stage lung cancer, for example, is treated with one hypo-fraction in one day.
The key to its success, he said, is that carbon ion therapy is localized, strong energy on target with less healthy tissue impacted.
Reflecting on his work, Tsujii said, “For the oncological aspect, there are several types of tumors which cannot be well treated with standard radiotherapy—pancreatic cancer, hidden neck cancer, rectal-pelvis cancer—and carbon ion therapy is very effective.”
He added that while carbon therapy is expensive at the beginning because of the capital cost of building a treatment center around a particle accelerator, with hypo-fractionated therapy it becomes less expensive, especially in comparison to proton therapy.
Photo courtesy of Hirohiko Tsujji
UT Southwestern oncologist Robert Timmerman has kept up with Tsujii and other practitioners’ results, and along with his UT Southwestern colleagues, he hopes to open one of the first carbon ion facilities in the United States. Timmerman pointed to the benefits of carbon therapy for patients with many tumors, a very large population, and for which, he said, drugs do not show encouraging results.
“If we really want to cure people with metastatic cancer who have hopefully more limited tumor or even multiple tumors, we need to re-add local therapy into the equation and that’s where carbon comes,” Timmerman said. After carbon treatment focusing on multiple tumors, drug therapies could work with mopping of the microtumors, he added.
Timmerman also is looking at the combining of carbon therapy with immunology treatments, and there is much current discussion and on heavy ion therapy’s spurring the body’s abscopal effect, whereby an effectively treated tumor catalyzes the body’s immune response to successfully suppress another tumor. His current work with immunotherapy with combining Stereotactoic Ablative Radiotherapy with immunology encourages him about this possibility.
The Future: Treating Synergies and the Testing Challenge
Several U.S. institutions are interested in building a carbon therapy center. Stanford University, for example, publicly announced in 2016 its interest in building a heavy ion center. Brookhaven National Laboratory is collaborating with the private Best Medical International and building an accelerator machine for its own carbon ion therapy center, perhaps in conjuction with an East Coast hospital. And the UT Southwestern and Colorado State University continue their interest in carbon ion centers.
It would have state-of-the-art imaging to verify the patient’s anatomy at time of delivery.
UT Southwestern oncologist Arnold Palombo, who shares his colleagues’ passion for a facility, believes the venture would be a bioengineering enterprise. "Bioengineering is here to actually get these machines and morph them with the medical doctor needs to make a machine that is specific to heavy ion therapy," he said.
He and Story are thinking about state of the center’s equipment. “It would have state-of-the-art imaging to verify the patient’s anatomy at time of delivery,” Palombo said. Story and Palombo both said a facility would need a light and nimble gantry, a technology currently undergoing miniaturization, to best serve patient needs.
"[A] new rotational gantry allows you to optimize the avoidance of critical normal tissue structures," while treating a patient with ion therapy, Story said.
Still, even with sophisticated combinations of immunology, chemotherapy, radiology and other heavy ion beams, and new instrument advances, testing is a crucial challenge. While the data coming from Japan is quite good, researchers interviewed for this article said it is typically not based on random testing. In Japan, the "equipoise" principle governs, which holds that a treatment that a physician is convinced is superior cannot be denied to a patient just to compare treatment results. This means that people who are deemed likely to benefit from carbon ion therapy will receive that therapy—as opposed to receiving an alternative therapy, which is necessary in order to test the efficacy of carbon treatment in a phase 3 clinical trial.
In the United States, too, where great value is placed on phase 3 clinical trial data, the equipoise principle is influential and may make it hard to obtain that data. How to get then some degree of Phase 3 trial data, overcome cost concerns, (which include health insurance reimbursement), get critical mass of expertise going to manage these centers, makes the future of U.S. carbon ion therapy something of a Catch-22.
But the proponents do have some ideas. Jac Nickoloff, a professor of cancer biology, heads the Environmental & Radiological Health Sciences at Colorado State University in Fort Collins, and he has been active in promoting a heavy ion therapy center in Colorado, working with his colleagues in developing research ties with National Institute of Radiological Sciences in Japan.
Nickoloff believes that one important bridge available now is conducting carbon ion and other ion research on cancer in dogs. Of the 75 million dogs in the United States, approximately half will get cancer, and most are not treated, according to Nickoloff. The Colorado State University College of Veterinary Medicine and Biomedical Sciences Animal Cancer Center leads the world in treating dogs with radiation therapy and chemotherapy. The dogs’ large spontaneous tumors resemble human cancers more than mouse models, Nickoloff said, and dogs have functional immune systems and organs more similarly sized to humans’.
Photo courtesy Jack Nickoloff
"The dog model is far superior to mice," Nickoloff said, though he emphasized that he envisions dog therapy and canine clinical trials with carbon ion therapy -- not some form of inhumane animal experimentation. "The veterinary side of the equation can play a very important role in translating and speeding translation from the cells and mice research to the people," Nickoloff said. Tsujii, too, is impressed with Colorado State University's canine cancer research and hopes this line of research will advance.
Blakely of Lawrence Berkeley Laboratory offered another possible bridge for the research gap. She pointed out that with new capacities for theoretical modeling, researchers can take large data sets of clinical information about human and ions treatment—which might be incomplete and anecdotal—and match it with more complete animal studies for specialists to make good estimates for dose and treatment. She points to Japanese success with this data approach, contributing to setting lower dose fraction numbers with stronger dosage per fraction. "It is a comparative science that has limitations statistically but when you garner as many different kinds of data that you can acquire, it reveals a trend for the best choice of dose fraction and total dose required to improve survival outcome," Blakely explained.
Timmerman has a testing idea, too, for a "dilution randomized trial" in which everyone undergoing treatment would get carbon treatment but in varying escalations in combinations of carbon ion with other treatments.
"The beauty of this design is that everyone would get carbon," Timmerman said, though the degree would vary. "That way everyone would get equipoise."
We have only 10 heavy ions center in the world, so, there are tons of things to do.
And then there is always the possibility of traditional Phase 3 research commencing with a new building. In the international realm, for example, Japan’s Gumma University, UT Southwestern and Italy National Centre of Oncological Hadrontherapy (CNAO) are collaborating on an international pancreatic cancer randomized test.
Overall, the experts contacted for this article were bullish in their hopes for the future.
"We have only 10 heavy ions center in the world, so, there are tons of things to do," said Palombo, one of the oncologists from UT Southwestern. "Imaging needs to be improved, delivery speed needs to be improved, and [with] some of the parameters [of] these systems there are ways to improve."
"It’ll take a combination of an accelerator physicist, a particle physicist and a medical doctor [to] drive it such that the next generation of machines will be patient-tuned."