Proton therapy: the current status of the clinical evidences – by Dongryul Oh

Precision and Future Medicine 2019

Proton Therapy Clinical Evidences – Dongryul Oh

The dosimetric advantages of proton therapy—compared with photon therapy—have been clearly defined in many comparison studies involving various tumor sites. There are now accumulating clinical data demonstrating that this dosimetric advantage can lead to better outcomes such as reduced RT toxicity and improved treatment outcomes. 

Pediatric Tumors

RT has an important role in treating pediatric tumors including central nervous system (CNS) tumors, extra-cranial sarcomas, neuroblastoma, and hematopoietic tumors. Long-term toxicities, including secondary malignancies, neurocognitive dysfunctions, growth and musculoskeletal problems, and cardiac problems, are major concerns in pediatric patients who undergo RT. There have been many efforts to reduce the RT dose and volume to avoid these RT-related toxicities.

Proton therapy is one of the best options to reduce unnecessary irradiation dose and volume in pediatric patients.

More than 30 pediatric tumor types were treated, mainly with curative intent: 48% were CNS, 25% extra-cranial sarcomas, 7% neuroblastoma, and 5% hematopoietic tumors

Head and Neck Tumors

Retrospective data have demonstrated better local control (LC) and overall survival (OS) with proton therapy than with photon therapy including IMRT and stereotactic body radiation therapy (SBRT).

Proton therapy has also demonstrated better survival rates in nasal cavity and paranasal sinus tumors.

In oropharyngeal cancers, proton therapy can reduce toxicity to normal tissues.

Proton therapy can also reduce toxicities in unilateral irradiation, such as in cases involving major salivary gland tumor and oral cavity cancers, because the exit dose of the proton beam is essentially negligible

CNS tumors

Cognitive impairment has been one of major concerns following RT for CNS tumors. Proton therapy has a potential benefit to reduce the irradiated dose to normal brain tissue to prevent cognitive dysfunction. In addition, a dose escalation could be possible in radioresistant brain tumors such as high-grade gliomas.

Gastrointestinal tumors

Proton therapy can spare the surrounding normal tissues when it is used to treat gastrointestinal tumors. In the management of hepatocellular carcinoma (HCC), it is very important to spare liver function. Because the liver is an organ with parallel functional subunit in the model of radiation response of normal tissues, liver toxicity is more sensitive to irradiated volume. Proton therapy has a major advantage in reducing the irradiated volume of remnant liver when irradiating the tumor. In many retrospective trials, proton therapy resulted in favorable outcomes.

Re-irradiation

Proton therapy has the advantage of irradiating the target while reducing the dose to the surrounding normal tissues; thus, it has a potential benefit in re-irradiation. Many retrospective studies investigating re-irradiation in various tumor sites have been reported.

Non-Small Cell Lung Cancer

Low-dose shower is a major risk for radiation pneumonitis (RP) when treating non-small cell lung cancer (NSCLC) with photon therapy. If the lateral beam placement is avoided to reduce the lung dose, the irradiated dose to heart is consequently increased and results in increased cardiac death in long-term follow-up. In many dosimetric studies, proton therapy demonstrated advantages in lung and heart dose compared with photon therapy. Several clinical studies have reported treatment outcomes and toxicities of proton therapy in early-stage disease, locally advanced disease, re-irradiation, and in postoperative settings 

Indications for Proton Therapy

American Society for Radiation Oncology (ASTRO)  has updated the recommendations for insurance coverage. The ASTRO recommendation is based on four selection criteria:

  1. a decrease in dose inhomogeneity in a large treatment volume is required to avoid an excessive dose “hotspot” within the treated volume to lessen the risk for excessive early or late normal tissue toxicity;
  2. the target volume is in close proximity to ≥1 critical structure(s), and a steep dose gradient outside the target must be achieved to avoid exceeding the tolerance dose to the critical structure(s);
  3. a photon-based technique would increase the probability of clinically meaningful normal tissue toxicity by exceeding an integral dose-based metric associated with toxicity;
  4. and, finally, the same or an immediately adjacent area has been previously irradiated, and the dose distribution in the patient must be carefully modelled to avoid exceeding the cumulative tolerance dose to nearby normal tissues.

Based on the above medical necessity requirements and published clinical data, group 1, which is recommended coverage is listed as follows:

  • ocular tumors, including intraocular melanomas;
  • skull base tumors, primary or metastatic tumors of the spine, where spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated;
  • hepatocellular cancer;
  • pediatric tumors;
  • patients with genetic syndromes making total volume of radiation minimization crucial;
  • malignant and benign primary CNS tumors;
  • advanced and/or unresectable H&N cancers;
  • the paranasal sinuses and other accessory sinuses cancers;
  • non-metastatic retroperitoneal sarcomas;
  • and cases requiring re-irradiation.

Read the full study on Precision and Future Medicine 2019

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Proton therapy for cancer lowers risk of side effects

by Julia Evangelou Strait, Washington University School of Medicine

Proton therapy results in fewer side effects than traditional X-ray radiation therapy for many cancer patients, according to a new study led by Washington University School of Medicine in St. Louis and the Perelman School of Medicine at University of Pennsylvania. Even with reduced side effects, proton therapy resulted in cure rates similar to those of X-ray radiation therapy.

Proton therapy for cancer lowers risk of side effects
A new study led by Brian Baumann, M.D., of Washington University School of Medicine in St. Louis, found that proton therapy (bottom) is associated with fewer severe side effects than conventional X-ray radiation therapy (top) for many cancer patients. Credit: Brian Baumann/Mike Worful

The study is the first major side-by-side comparison of side effects related to proton therapy and X-ray radiation therapy. It included almost 1,500 patients receiving combined chemotherapy and radiation therapy for lung, brain, head and neck, gastrointestinal and gynecologic cancers that had not yet spread to other parts of the body. Such patients receive both radiation and chemotherapy, a treatment regimen that often cures nonmetastatic cancer. But it also causes severe side effects—such as difficulty swallowing, nausea and diarrhea—that reduce quality of life and can, in some cases, require hospitalization.

After controlling for differences between the groups, such as age and additional medical problems, the researchers found that patients receiving proton therapy experienced a two-thirds reduction in the relative risk of severe side effects within 90 days of treatment, compared with patients receiving X-ray radiation therapy. Forty-five of 391 patients receiving proton therapy experienced a severe side effect in the 90-day time frame (11.5 percent). In the X-ray radiation therapy group, 301 of 1,092 patients experienced a severe side effect in the same period (27.6 percent). Patient data on side effects were gathered as the trial was ongoing, rather than after the fact.

“Proton therapy was associated with a substantial reduction in the rates of severe acute side effects—those that cause unplanned hospitalizations or trips to the emergency room—compared with conventional photon, or X-ray, radiation for patients treated with concurrent radiation and chemotherapy,” said Baumann, an assistant professor of radiation oncology at Washington University and an adjunct assistant professor of radiation oncology at Penn. “The opportunity to reduce the risk of severe side effects for patients and thereby improve their quality of life is very exciting to me. While there have been other studies suggesting that proton therapy may have fewer side effects, we were somewhat surprised by the large magnitude of the benefit.”

The researchers focused their study on what are called grade 3 adverse events, which are severe enough to require hospitalization. These can include pain, difficulty swallowing that might result in weight loss, difficulty breathing, and nausea and diarrhea severe enough to cause dehydration.

The researchers also found no differences between the two groups in survival, suggesting that proton therapy was just as effective in treating the cancer even as it caused fewer side effects. Overall survival at one year for the proton therapy group was 83 percent of patients versus 81 percent for the X-ray radiation therapy group. This difference was not statistically significant.

This study is the first large review of data across several cancer types to show a reduced side-effect profile for proton therapy compared with X-ray radiation therapy for patients receiving combined chemotherapy and radiation. Both types of radiation therapy are approved by the Food and Drug Administration for cancer treatment. Protons are relatively heavy, positively charged particles that hit their target and stop. X-ray beams consist of photons, which are much smaller particles that have almost no mass, allowing them to travel all the way through the body, passing through healthy tissue on the way out.

https://medicalxpress.com/news/2019-05-proton-therapy-cancer-lowers-side.html

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Proton beam therapy for gastrointestinal cancers: past, present, and future

Shahed N. Badiyan1, Christopher L. Hallemeier2, Steven H. Lin3, Matthew D. Hall4, Michael D. Chuong4

Despite the conformality of modern X-ray therapy limiting high dose received by normal tissues the physical properties of X-rays make it impossible to avoid dose being delivered distal to the target. This “exit dose” is likely clinically significant especially for patients with gastrointestinal (GI) cancers when considering that even low dose received by the heart, lungs, bowel, and other radiosensitive structures can lead to morbidity and even may affect long-term tumor control. In contrast, proton beam therapy (PBT) delivers no “exit dose” and a growing body of literature suggests that this may improve clinical outcomes by reducing toxicity and even allowing for safe dose intensification to enhance tumor control. While there are not yet robust prospective data demonstrating the role of PBT for GI cancers, emerging retrospective data provide a strong rationale for continued study of how PBT may improve the therapeutic ratio for these patients. Here we review these data as well as discuss ongoing clinical trials of PBT for GI cancers

Figure 1 Significant normal tissue sparing with proton beam therapy (PBT) compared to intensity modulated radiation therapy (IMRT) for treatment of esophageal cancer. Dmax, maximum point dose; Vx, volume getting x dose in Gy; MLD, mean lung dose; MHD, mean heart dose; MLivD, mean liver dose; MKD, mean kidney dose.

Figure 2 A patient with a 20-cm localized hepatocellular carcinoma replacing the entire right lobe of the liver who was treated with proton beam therapy (PBT) (left images) to a dose of 58.05 Gy (RBE). In the right images, a comparison plan with X-ray intensity modulated radiotherapy (IMRT) is shown. PBT (vs. IMRT) resulted in significant reduction in dose to the uninvolved liver (mean dose, 13 vs. 27 Gy), stomach (mean dose, 0 vs. 18 Gy), and right kidney (volume receiving 20 Gy, 26% vs. 48%).

Figure 3 Significant sparing of abdominal organs with proton beam therapy (PBT, right) compared to X-ray therapy (left) in a patient with pancreatic

Conclusions

Given the accruing data showing a strong relationship between clinical outcomes and low dose received by organs at risk, there is a strong rationale to consider Proton Beam Therapy for patients with cancers of the foregut. While not all patients likely benefit from PBT, mounting retrospective data indicate that ongoing and future clinical trials may demonstrate that PBT provides clinically meaningful benefit for a subset of patients with Gastro Intestinal cancers.

Journal of Gastrointestinal Oncology Vol 9, No 5 (October 2018) 

http://jgo.amegroups.com/article/view/17379/html

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