Systematic Review: Charged-Particle Radiation Therapy for Cancer

Results

Charged-Particle Radiation Therapy and Alternative Contemporary Conformal Radiation Therapy Techniques

Contemporary conformal radiation therapy techniques have better dose distribution than conventional external photon radiation therapy; investigators claim that the former offer better tumor control because of safe dose escalation and fewer radiation-induced complications because of superior sparing of normal tissue. This makes conformal radiation therapy particularly appealing for surgically unapproachable tumors located adjacent to critical structures, such as the brainstem, cranial nerves, or the spinal cord.

Charged-Particle Radiation Therapy

Charged-particle radiation therapy uses beams of protons or other charged particles, such as helium, carbon, neon, or silicon, but only protons and carbon ions are currently in clinical use Charged particles represent advancement over photons because the former have superior depth–dose distribution. Photons or electron beams deposit most of their energy near the surface (skin and normal tissues), with progressively smaller dose at larger depths, where the tumor may be located. In addition, photons continue to deposit the dose of radiation in normal tissues beyond the tumor. In contrast, charged particles deposit a low dose near the surface and almost all their energy in the final millimeters of their trajectory in the tumor; tissues beyond the tumor location receive very little of the dose. This pattern results in a sharp and localized peak dose, known as the Bragg peak. The initial energy of the charged particles determines how deep in the body the Bragg peak will form. The intensity of the beam—that is, how many particles traverse a particular area in unit time—determines the dose that will be deposited to the tissues. By adjusting the energy of the charged particles and the intensity of the beam, one can deliver prespecified doses anywhere in the body with high precision. If the tumor is larger than the Bragg peak width, multiple Bragg peaks of different energies and intensities are combined, forming a spread-out Bragg peak with a constant dose distribution in the tumor and a steep dose decline at the end

Because charged particles damage cell DNA in qualitatively different ways than photons or electrons, the same amount of physical radiation can have much more pronounced biological effects, resulting in greater cellular damage. The relative biological effectiveness (RBE) is the ratio of the dose required to produce a specific biological effect, with photons as reference radiation, to the charged particle dose that is required to achieve the same biological effect. The RBE of protons is approximately 1.1, which means that protons result in approximately 10% more biological damage per unit dose than photons. Heavier particles can have different RBE and dose distribution characteristics. For example, carbon ions have an RBE of approximately 4. Charged particles have greater biological effectiveness than photon beams because they have a higher rate of energy deposition to tissues (higher linear energy transfer). Generally, the higher the linear energy transfer of the radiation, the greater the relative ability to damage cellular DNA. An additional advantage of high linear energy transfer radiation is that it can affect hypoxic cells within a tumor, which are generally resistant to low linear energy transfer radiation, such as photons and electrons

Charged-particle radiation therapy is expected to deliver biologically equivalent doses more precisely and with less radiation-induced morbidity than conventional photon radiation therapy. This could be beneficial in children, because they are considered more susceptible to radiation side effects and because development of secondary cancer is a concern. It is unclear whether the claimed high precision in dose delivery is beneficial, let alone mandatory, for all indications and particularly in adults. Several investigators have suggested that proton-beam radiation therapy may be indicated in approximately 15% of patients undergoing irradiation

A common argument against the broader use of charged-particle radiation therapy is its high cost. Studies found proton-beam radiation therapy to be more expensive than conventional photon radiation and evidence on cost-effectiveness is generally scarce. In addition, the number of facilities that can provide charged-particle radiation therapy is limited. Seven proton-beam facilities are in operation in the United States as of 8 July 2009, and at least 4 are currently under construction, at a cost of $100 to $225 million. The facilities host the equipment for generation of the charged particles, their acceleration, transportation to typically 3 to 4 treatment rooms, and proper delivery to the patients according to the planned treatment scheme. Private companies have announced efforts to build less expensive, small-scale facilities that would fit all the necessary equipment into a single treatment room at a cost of about $20 million. Several U.S. hospitals have expressed interest in acquiring these small-scale facilities.

Intensity-Modulated Photon Radiation Therapy

Since its introduction more than a decade ago, intensity-modulated photon radiation therapy has spread worldwide and is currently available in most radiation therapy departments . In the United States, it became available to more than 70% of radiation oncologists within 5 years, despite sparse evidence of its benefit from prospective randomized studies and higher costs this phenomenon has triggered concerns about similar adoption of charged-particle radiation therapy. One concern about intensity-modulated photon radiation therapy is that its higher integral dose and total increased volume of radiation exposure may increase the risk for secondary cancer and complications in normal tissue. Nevertheless, intensity-modulated photon radiation therapy is considered a standard of care for many cancer indications.

Stereotactic Radiosurgery and Stereotactic Body Radiotherapy

Stereotactic radiosurgery uses multiple low-intensity photon beams that converge to the same area and effectively deliver a single high dose of radiation to a target lesion in the central nervous system. With advances in imaging technologies and immobilization techniques that take better account of tumor motions caused by respiration, it is now possible to use stereotactic radiotherapy for cancer located outside the central nervous system. This radiotherapy technique is considered one of several approaches to delivering ablative radiation doses directly to the target lesion with acceptable toxicity in adjacent normal tissues.

Brachytherapy and Intraoperative Radiation Therapy

Brachytherapy and intraoperative radiation therapy have been used widely and have specific indications. Brachytherapy is used to treat cancer at many different sites and may be more conformal than charged-particle radiation therapy because the radioactive sources are implanted directly into the tumor or postoperative cavity. It is one of the standard treatment options for prostate cancer and is a primary treatment option for some types of gynecologic cancer. However, brachytherapy requires at least a minor invasive procedure to insert radioactive sources, and thus similar limitations may apply in terms of its applicability to tumors in proximity to critical normal structures. Nevertheless, some studies indicate that brachytherapy may be more cost-effective than external radiation therapy. In contrast to brachytherapy, where radioactive sources are implanted either temporarily or permanently, intraoperative radiation therapy is typically defined by delivery of a single fraction of external-beam radiation in the operating room suite. It requires dedicated radiation sources in the operating room, substantial shielding to protect operating room staff, and great logistical support; its overall utilization is therefore limited. Clinical outcome results have been reported in single-institution retrospective studies

Systematic Review of Charged-Particle Radiation Therapy

Literature Selection and Overview of Current Information

Comparative Studies

Randomized Trials.

Primary outcomes were explicitly stated in only 3 trials, which also reported a priori sample size calculations. No trials were designed to have a sufficiently large sample size or sufficient duration of follow-up and thus failed to demonstrate statistically significant difference in overall or cancer-specific survival, whereas 4 trials reported statistically significant differences in various other outcomes. In 3 of 4 trials, the results favored the charged-particle radiation therapy group (better local control with helium ions than with brachytherapy for uveal melanoma [local control rates at last follow-up, 100% vs. 87%; P < 0.05])  or the group with the most intensive intervention (fewer eye enucleations for proton irradiation with laser thermotherapy versus proton irradiation alone for uveal melanoma [5-year enucleation rates, 3% vs. 20%; P = 0.02], and better local control [5-year local control rates, 67% vs. 48%; P < 0.001] and freedom from biochemical failure of prostate cancer [freedom from biochemical failure, 80% vs. 61%; P < 0.001] with higher versus lower dose of protons). The fourth trial reported a significantly lower incidence of rectal bleeding with the conventional approach (lower cumulative dose) than with charged-particle radiation therapy (higher total dose) in patients with prostate cancer (8-year bleeding incidence rates, 12% vs. 32%; P = 0.002)

Nonrandomized Comparative Studies.

Thirteen articles reported on 9 nonrandomized comparative studies in an estimated 4086 unique patients. Four studies compared charged-particle radiation therapy versus brachytherapy in uveal melanoma, 6 studies versus conventional photon radiation therapy in other types of cancer, and 3 studies versus surgery. None of the studies used advanced statistical analyses, such as propensity score matching or instrumental variable regressions, to better adjust for confounding. Overall, no study found that charged-particle radiation therapy is statistically significantly better than alternative treatments with respect to patient-relevant clinical outcomes.

Discussion

Charged-particle radiation therapy is an alternative mode of radiation delivery that is becoming increasingly available. The infrastructure necessary for large charged-particle radiation therapy facilities is substantial and costly, but several companies are developing smaller-scale (and less costly) equipment. The theoretical advantages of this type of radiation therapy over alternate options have yet to be demonstrated in clinical studies, especially for common types of cancer. Specifically, comparative evidence is lacking on the safety and effectiveness of charged-particle radiation therapy versus alternatives therapies. In contrast, we found several noncomparative studies that reported case series or experience of treatment strategies incorporating charged-particle radiation therapy on overlapping patients between studies.

The few available randomized trials mainly assessed intermediate outcomes. Investigators frequently compared lower and higher doses of the same charged particles, and they rarely compared this type of radiation therapy with other treatment modalities. Studies comparing charged-particle radiation therapy strategies with contemporary alternatives that do not include charged-particle radiation therapy would be more informative. From that perspective and despite the very limited treatment slots, comparisons of different protocols for charged-particle radiation therapy should not be the only comparisons evaluated. Although randomized evidence is lacking, nonrandomized comparative studies in general failed to demonstrate a survival advantage of charged-particle radiation therapy over conventional radiation therapy.

Previous systematic reviews have also uniformly pointed out the paucity of comparative evidence that demonstrates incremental value of charged-particle radiation therapy over conventional photon radiation therapy. Some of these reviews suggest that charged-particle radiation therapy may be a good alternative modality, especially for selected rare and specific types of cancer (such as head and neck cancer) for which conventional treatments would cause substantial risk to critical structures in close proximity to the tumor. Our findings concur with these suggestions.

Charged-particle radiation therapy may become much more accessible in the near future, as more institutions acquire the infrastructure and knowledge to administer it. As its availability increases, costs may decrease. We expect that such trends will inevitably increase the number of patients who will be treated with charged-particle irradiation. A central issue is whether the comparative effectiveness and safety of charged-particle radiation therapy versus other radiation therapy alternatives should be empirically documented before wider indications for charged-particle radiation therapy are endorsed. Several authorities have argued that this is not necessary. Their rationale is that the dose distributions with charged particles are almost universally superior to those attained with photon beams; the biological effects of charged particles are very similar to those of photons, and therefore tissue responses to charged-particle irradiation are already known; and it is self-evident that sparing normal tissues from irradiation is beneficial.

However, this line of reasoning equates precision in radiation therapy delivery with clinical outcomes. In addition, despite a very favorable and strong pathophysiologic rationale for effectiveness benefit, interventions have turned out to be harmful when evaluated in randomized, controlled trials (for example, antiarrhythmics for premature ventricular contractions and erythropoietin for anemia in chronic kidney disease). In reality, it is very likely that there are many instances of clinical equipoise between charged-particle radiation therapy and other modalities, for both common and rare types of cancer. For example, for many patients with prostate cancer, it is unclear whether conformal radiation therapy in general is more efficacious or safe than conventional radiation therapy. For anatomically challenging tumors that are adjacent to critical structures, nonconformal radiation therapy may be contraindicated. However, it is unknown how charged-particle radiation therapy compares with more available and less expensive types of conformal radiation therapy, such as intensity-modulated radiation therapy, brachytherapy, or stereotactic radiation therapy. Again, a major issue is whether any differences are large enough to justify the differences in costs.

We believe that comparative studies, preferably randomized, controlled trials if feasible, coupled with concurrent economic analyses would be useful to inform the optional use of these technologies. Apart from randomized trials, proper analyses of nonrandomized comparisons in well-characterized patient cohorts may also be helpful. Finally, the unadjusted treatment effects are very large in a nonrandomized study, it is unlikely that these effects are entirely attributable to biases; in such a scenario, a randomized comparison may not be necessary

In summary, several studies of charged-particle radiation therapy for cancer have been published. However, these studies do not document the circumstances in contemporary treatment strategies under which radiation therapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible), are needed to document the theoretical advantages of charged-particle radiation therapy in specific clinical situations.