Carbon ion radiation therapy for prostate cancer

Move over proton, carbon ion is here and the results so far are excellent. Actually, carbon ion radiation therapy has been around for some time, but the cost and the technological requirements have been prohibitive. There are only five treatment centers worldwide, and all are government subsidized: three in Japan (Chiba, Hyogo, and Gunma), one in Germany (Heidelberg), and one in China (Lanzhou). The newest one (built in Gunma, Japan, in 2012) took advantage of technological innovations to build a treatment center that is house-sized rather than football-field sized, and at one-third the cost. This brings the cost into line with most proton treatment centers in the US.

Carbon ion beams offer several radiobiological advantages over protons or photons. The near speed-of-light carbon ions are thousands of times more destructive of cancer cells. They cause multiple irreparable breaks in the DNA of even the most radio-resistant cancer cells. Because the carbon ions do not depend on environmental oxygen to do their cell killing, hypoxia, a low-oxygen condition that can protect cancer cells from proton or photon damage, does not offer a challenge. For this reason, carbon ion, unlike proton, has been used as a monotherapy for high-risk prostate cancer (without combining with X-ray IMRT), and has been found to be effective.

Toxicity is theoretically lower with carbon ions. Compared to protons or photons, it takes much lower doses to have the same effect, and because its Bragg peak effect (at 100 percent) is greater than protons (at 99 percent), there is no damage to healthy tissue forward of the beam from failure to stop. There is greater production of secondary ions from nuclear reactions past the beam, but they have little biological impact. Unlike protons, however, toxic secondary neutrons are not created. Proton therapy often requires the use of spread-out Bragg peaks to treat large-sized volumes like the prostate. This compromises the tissue-sparing advantage of the sharp Bragg peak. However, carbon ions have very high linear energy transfer (LET) and destroy the tumor for a much longer distance within the prostate. This quality is a big advantage in treating organs deep inside the body.

Carbon ions are 12 times more massive than protons. The higher mass means it takes a lot more energy to accelerate a carbon ion beam to the point where it can penetrate deep into the prostate without being absorbed by surface tissues. That’s why it has taken football-field sized cyclotrons to produce the beam. The huge inertia of the beam also makes it more difficult to bend and deliver to the right place in the patient. This requires room-sized gantries with powerful electromagnets. But the upside is that the beam is not easily scattered, as protons are, so the beam goes exactly where it is aimed.

The high relative biological effectiveness (RBE) of the carbon ion beam lends itself well to hypofractionation. As we have seen with HDR brachytherapy, SBRT, and hypofractionated IMRT, prostate cancer is unusual in that it is more efficiently killed by fewer higher doses of radiation (hypofractionation) than by longer courses of lower dose radiation. This quality is called a “low alpha/beta ratio,” which is about 1.5 for prostate cancer cells. Because the alpha/beta ratio of prostate cancer cells is so much lower than most of the healthy tissues of the urinary tract and rectum (with an alpha/beta ratio of about 10), it creates a therapeutic advantage; the total dose for cancer control is much lower than would otherwise be required, and the acute toxicity to healthy tissues is reduced at the same time. Carbon ions have traditionally been delivered as 66 GyE in 20 treatments or fractions. The Chiba Carbon Ion Therapy facility has had successful trials of even greater hypofractionation: 58 GyE in 16 fractions, and 52 GyE in 12 fractions.

It’s one thing to be safe and effective in theory, and quite another to be safe and effective in actual clinical practice. Could the smaller, less expensive Gunma facility replicate the excellent results reported at Heidelberg and Chiba? They prospectively treated 76 patients with 58 GyE in 16 fractions. With median follow up of 51 months, Ishikawa et al. report that:

  • 4-year biochemical relapse-free survival was 95 percent.
  • Grade 2 gastrointestinal (GI) toxicity in 1.3 percent.
  • Grade 2 genitourinary (GU) toxicity in 6.6 percent.
  • Patient-reported health-related quality of life was well maintained.

Unfortunately, the authors did not report breakdowns by risk group on this small sample. It would be especially useful to see the effects on sexual function.

For comparison, the larger facility at Chiba reported outcomes last year on 1,144 patients treated between 2000 and 2012 who had the following characteristics:

  • 197 were “low risk,” and received no ADT.
  • 362 were “intermediate risk,” and received 6 months of neoadjuvant ADT.
  • 585 were “high risk,” and received 6 months of neoadjuvant ADT and at least 18 months of adjuvant ADT.
  • Patients were treated with either 66 GyE in 20 fractions or 58 GyE in 16 fractions.
  • The patients’ median age was 68 years.

After median follow up of 49 months, Nomiya et al. report:

  • 5-year biochemical relapse-free survival was 91 percent.
  • Grade 2+ GI toxicity was 1.1 percent.
  • Grade 2+ GU toxicity was 6.5 percent.
  • Toxicity was less among those treated with the 16 fraction schedule

These results are nearly identical to those reported at Gunma, and are among the lowest we’ve seen for any radiation therapy.

The treatment of high-risk prostate cancer is especially intriguing. Carbon ions seem to be especially effective at treating cancers that are relatively impervious to treatment with X-rays or protons. It is possible that cancer stem cells, neuroendocrine cancer, and hypoxic tumors may be more easily destroyed. In another study from Chiba, Shimazaki et al. reported that, with a median follow up of 87 months, the biochemical failure-free rate among high-risk patients was 85 percent. This compares favorably to the 68 percent rate reported by Spratt et al. from Memorial Sloan-Kettering Cancer Center at 7 years using extra-high-dose (86.4 Gy) X-ray IMRT.

The Heidelberg carbon ion treatment facility has only, so far, reported preliminary results on 14 intermediate-risk patients treated with a combination of IMRT (60 Gy in 30 fractions) with a carbon ion boost (18 GyE in 6 fractions) to the prostate. Most (12 of 14 patients) also had neoadjuvant ADT. After a median 28 months of follow up, Nikoghosyan et al. report:

  • 3-year biochemical recurrence-free survival was 86 percent
  • There was no acute Grade 2 GI toxicity.
  • Acute Grade 2 GU toxicity was 36 percent and resolved in most (12 of 14 patients) by the time of the first follow up.

The Gunma results so far show that this therapy is both safe and effective, and can be accomplished at lower cost. Japan has already started building several new facilities, which will be coming on-line shortly. This is not a project with great profit potential for private industry. The capital costs are enormous, and if there are only 12 treatments necessary, the charge per person would have to be unreasonable to recoup costs. None have yet been announced for the US, but given the excellent outcomes, there may be a role for intermediate-risk and especially for high-risk patients.

The US first demonstrated the efficacy of carbon ion treatment at the Lawrence Berkeley National Laboratory in the 1970s and 80s. This was the proof of concept that led Germany and Japan to invest in this treatment. The Department of Energy has encouraged renewed US interest, and there is a proposal for a national particle beam R&D center at Walter Reed. The proposed R&D center, which would cost approximately $150 million, would exist to advance both research and treatment options for tumors that:

  • Exhibited a high-risk of local failure post photon (or proton) RT
  • Were radio-unresponsive due to histology, hypoxia, and other factors
  • Were recurrent
  • Were efficient at repairing cellular damage
  • Were adjacent to critical normal structures, especially if resection could lead to a substantial loss of organ function.

Starting with a national R&D center here in the US may provide the data, technology, and cost improvements that private industry would need to justify investment. Perhaps with that, and the enhanced therapeutic ratio of carbon ions, it may make more sense on a cost/benefit basis than the current spate of proton treatment centers.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

8 Responses

  1. Some readers may remember that we first commented on the possible potential of carbon ion beam therapy back in 2013. That article offered a couple of additional links to background information that may be of interest to a limited number of readers.

  2. To this non-expert and gullible punter these results seem amazingly good, to the extent that if I still had a prostate that needed treating I would be fleeing from the proton beam center and trying to find a carbon ion facility that would treat me.

    In the Sitemaster’s 2013 article you concluded by saying:

    “It would seem to us that we would need to see some pretty compelling data about the clinical benefits of carbon ion radiation therapy before we started to use process like this in the management of prostate cancer on a regular basis.”

    I presume you would say that these results are interesting, encouraging, but the studies are too small to constitute “compelling”?

  3. Dear James:

    I think that at the moment I would limit myself to “interesting”. “Encouraging” would be a term I might use if we could see large scale data (particularly in well-characterized, high-risk patients) from facilities like the one at Gunma — at a cost that would equate to something like $40,000 per treatment or less in the USA. “Compelling” is another step entirely.

  4. Japan and Germany are reportedly paying about $20,000 per patient in reimbursement costs. I don’t know how they arrived at that figure, or whether it covers only variable costs. An important benefit of a national R&D center would be that they can select patients according to those pre-established criteria mentioned above, and won’t be tempted by a profit motive (or patient demand) to market to patients who would be equally well served by other treatments or active surveillance.

  5. Let’s say that any one of the centers in Germany or Japan is treating 500 patients per year or 2 patients per day for 5 days a week (which they almost certainly aren’t). At $20,000 per patient, that would give such a center an annual revenue per center of $10 million.

    One estimate that I have seen suggests that the cost to build a carbon ion facility here in the USA would be well in excess of $100 million. It can’t have cost any less than that to build the ones in Japan and Germany.

    On that basis, I think we can safely assume that the $20,000 per patient being paid by the Japanese and German governments per patient is only covering (at best) the costs for the actual treatment of the individual patients, and that the original building and development costs have been written off.

  6. I am expecting carbon ion therapy to evolve in the direction of hybrid systems, in which carbon ion capability (and conceivably other hadrons) are added, first, to existing and planned proton treatment centers. This may be in the form of hybrid particle generation being included in the same beam generator, or in the form of separate generators mounted on the same (suitably modified) gantry. (Ion Beam Applications, S.A. already has such a hybrid.). It is even conceivable that hybrid capability could in the future be brought to certain large LINAC facilities where the room and shielding configuration could allow it, or be modified to embrace it. The economics of such hybrid systems may not be as daunting as the comments above appear to suggest, because the larger spectrum of treatment options would likely increase the patient load. On the subject of future treatment economics, one may also mention Mevion Medical Systems, which is now delivering compact (in configuration and price) proton systems and presumably could use similar configurations for carbon ion or hybrid beams.

  7. I am rather new to divining the positives and negatives of the present-day radiation therapies in treating prostate cancer. From the above article on carbon therapy and from what (I think) I understand about SBRT-level hypofractionation (e.g., 35 Gy/5 fractions up to 38 Gy/4 fractions), the carbon therapy discussed above and SBRT seem to be providing similar bDFS for low- and intermediate-risk patients, at least out to 7 years or so. However, the GU and GI side-effects would seem to be somewhat reduced for carbon therapy compared to SBRT. Hence, would its present advantage over SBRT, if any, rest in its lower level of side effects?

  8. T. Petrie:

    There is absolutely no reason to use a big, expensive machine like this to treat favorable-risk prostate cancer that is controlled with low side effects by SBRT or other methods. The advantage over SBRT may lie in the kinds of prostate cancer that carbon ion seems to treat exceptionally well, especially those with the “high risk” tumor characteristics listed at the end of the article. The only way to know for sure is to do a randomized, comparative clinical trial of both in high-risk men. SBRT has itself only recently been used for this group.

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