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

Montefiore Study May Help Establish Patient Criteria for Proton Therapy

N. Patrik Brodin, PhD

Data supporting the efficacy of proton therapy are robust for pediatric cancers, brain and base-of-skull tumors, and complex-shaped tumors near critical structures (…)

Proton therapy has emerged as an attractive option for patients with head and neck cancer. This is due to proton therapy beam technology, which precisely destroys cancers with an unmatched ability to stop at precise locations within the body.

Protons also have significantly fewer adverse effects (AEs) and toxicities than most other cancer therapies, because of the protons’ unique ability to sculpt radiation doses according to the shapes and sizes of tumors. This is particularly important for head and neck cancers, which frequently are close to or impeding on vocal cords, air passageways, swallowing muscles, salivary glands, and the oral mucosa. The opportunity to preserve healthy tissue is considerable.

AEs estimated to be significantly less prominent include swallowing difficulties, inflammation of the esophagus, and reduced saliva production. For people suffering from head and neck cancer and their families, the ability to avoid these types of complications makes an overwhelmingly important difference in QoL.

Younger patients, non-smokers, and patients with HPV p16- positive tumors will most likely benefit from proton therapy (…)

The highest expense in cancer therapy involves the regrowth of cancer—large sums are required to prolong survival and maintain QoL. By increasing cure rates and improving patients’ QoL, we can increase cost-effectiveness.

It is important for healthcare providers not only to educate our patients and their families about each treatment’s ability to destroy cancers, but also to manage expectations about different treatments and what life may look like “post cancer.”

Proton therapy is one of the most modern therapies available, and its ability to minimize AEs such as trouble swallowing, reduced ability to eat, dental problems, and difficulty digesting food can’t be understated for some of our patients (…) By increasing cure rates and improving patients’ Quality of Life, we can increase cost-effectiveness.

https://www.onclive.com/publications/oncology-live/2019/vol-20-no-11/montefiore-study-may-help-establish-patient-criteria-for-proton-therapy

Clinical Outcomes of Recurrent Intracranial Meningiomas Treated with Proton Beam Reirradiation.

Brandon S. Imber, Brian Neal, Dana L. Casey, Heba Darwish, Andrew L. Lin, Oren Cahlon, Brian Chon, Henry Tsai, Eugen Hug, Yoshiya Yamada, and T. Jonathan Yang (2019) International Journal of Particle Therapy: Spring 2019, Vol. 5, No. 4, pp. 11-22.

Proton beam radiation therapy (PBRT) offers a dosimetric advantage for reRT, especially for patients with multiple prior courses of RT, owing to improved ability to spare toxicity to nearby normal structures.

PBRT reRT may be a relatively efficacious strategy for recurrent meningiomas, a patient population lacking durable therapeutic options. Even with significant prior radiation exposure, radionecrosis rates appear low. We feel that prospective investigation of the modality is warranted to validate incremental improvement over traditional photon RT.

Proton and photon comparative dosimetry for a 72-year-old man with an anaplastic meningioma of the right cavernous sinus. (A) Original photon IMRT plan, which delivered 59.4 Gy in conventional fractionation. (B) Nodular area of T1 post contrast enhancement posterior to the right carotid artery suggestive of in-field recurrence (yellow arrow). (C) Proton reirradiation plan delivered to 60 Gy(RBE) in 2 Gy(RBE) fractions with 2 beams and uniform scanning. (D) Hypothetical comparison reirradiation plan using photon VMAT (not delivered). (E) Cumulative dose delivered by using proton beam radiation therapy. (F) Hypothetical cumulative dose delivered had photon VMAT plan been delivered. (G) Isodose lines in Gy for plans in (A), (C), and (D). (H) Cumulative isodose lines in Gy(RBE) for plans in (E) and (F). Abbreviations: IMRT, intensity-modulated radiation therapy; VMAT, Volumetric Modulated Arc Therapy.

https://theijpt.org/doi/10.14338/IJPT-18-00045.1

Dosimetric studies show that proton therapy can reduce the low/intermediate radiation dose to uninvolved tissue in children with low-grade glioma (LGG).

Outcomes Following Proton Therapy for Pediatric Low-Grade Glioma Indelicato, Daniel J. et al. International Journal of Radiation Oncology • Biology • Physics , Volume 104 , Issue 1 , 149 – 156.

Low-grade gliomas (LGGs) are the most common brain tumors in children, with approximately 800 cases diagnosed each year in the United States. Management of these tumors depends on several elements, including host factors (eg, patient age and comorbidities) and disease characteristics (eg, tumor location and histologic subtype). With a long-term survival rate that exceeds 90%, therapy selection involves careful consideration of minimizing late toxicity from surgery, chemotherapy, and irradiation. Treatment side effects can be permanent or life threatening and include neurocognitive impairment, neurologic deficits, neurovascular compromise, neuroendocrine deficiency, and second malignancies.

Surgery, radiation therapy, and chemotherapy may be used as solitary therapies or in combination, offering different therapeutic ratios depending on the setting. As a result, establishing the ideal treatment choice and sequencing has historically been an area of controversy, presenting challenges that are further complicated by the emergence of molecular targets.

Several studies have attempted to mitigate the impact of late radiation toxicity through selective radiation avoidance, systematic reduction in the size of target volumes, and the use of advanced radiation techniques. Of these radiation techniques, proton therapy is particularly promising because it allows for reductions in the low and intermediate radiation dose to normal tissue outside of the target volume. Accordingly, LGGs in children are considered a “Group 1” indication for proton therapy according to the United States American Society for Radiation Oncology Model Policy, and they have become the third most common pediatric brain tumor type treated with proton therapy worldwide.

Compared with modern photon series, proton therapy reduces the radiation dose to developing brain tissue, diminishing acute toxicities without compromising disease control.

https://www.redjournal.org/article/S0360-3016(19)30162-2/pdf

What is the best therapeutic approach to a pediatric patient with a deep-seated brain Arteriovenous Malformations ?

Meling TRPatet G

Proton Therapy offers promising results with a more accurate radiation that avoids the surrounding tissue

Although brain arteriovenous malformations (bAVMs) account for a very small proportion of cerebral pathologies in the pediatric population, they are the cause of roughly 50% of spontaneous intracranial hemorrhages. Pediatric bAVMs tend to rupture more frequently and seem to have higher recurrence rates than bAVMs in adults. Thus, the management of pediatric bAVMs is particularly challenging. In general, the treatment options are conservative treatment, microsurgery, endovascular therapy (EVT), gamma knife radiosurgery (GKRS), proton-beam stereotactic radiosurgery (PSRS), or a combination of the above. In order to identify the best approach to deep-seated pediatric bAVMs, we performed a systematic review, according to the PRISMA guidelines. None of the options seem to offer a clear advantage over the others when used alone. Microsurgery provides the highest obliteration rate, but has higher incidence of neurological complications. EVT may play a role when used as adjuvant therapy, but as a stand-alone therapy, the efficacy is low and the long-term side effects of radiation from the multiple sessions required in deep-seated pediatric bAVMs are still unknown. GKRS has a low risk of complication, but the obliteration rates still leave much to be desired. Finally, PSRS offers promising results with a more accurate radiation that avoids the surrounding tissue, but data is limited due to its recent introduction. Overall, a multi-modal approach, or even an active surveillance, might be the most suitable when facing deep-seated bAVM, considering the difficulty of their management and the high risk of complications in the pediatric population.

Neurosurg Rev. 2019 Jun;42(2):409-416. https://www.ncbi.nlm.nih.gov/pubmed/30980204

What are the general eligibility criteria for proton therapy ?

Proton therapy works well for localized solid tumors, whether benign or malignant, so we can address and cure the tumor by treating that location. We try to limit ourselves to curative patients who have a good quality of life because they need to come daily for the treatments over potentially a long period. Some patients require as many as 45 treatments ; some as few as 4 or 5. Generally, it is a four- to eight-week course of treatment.

Many patients have previously been treated with conventional therapy, and the tumors came back. They have no options at this point, but we may be able to re-radiate those patients with proton therapy. 

There is no age restriction. Our patient population ranges from babies to very spry 95-year-olds. Proton therapy is becoming a mainstay for treating pediatric tumors. By sparing still-growing tissue in children, proton therapy can reduce growth defects and secondary tumors caused by traditional radiation. 

Learn more about the cancers we treat with Proton Therapy

Hydrogel Spacer Reduces Rectal Dose during Proton Therapy for Prostate Cancer: A Dosimetric Analysis

Praveen Polamraju, BS; Alexander F. Bagley, MD, PhD; Tyler Williamson, BS, CMD; X. Ronald Zhu, PhD; Steven J. Frank, MD

Patients receiving radiation therapy for prostate cancer are at risk of developing treatment-related rectal toxicity, particularly as hypofractionated and stereotactic ablative approaches have become more prominent. Toxicity can manifest as rectal bleeding or bowel urgency, and the risk correlates with dosimetric parameters such as overall dose and the volume of rectum receiving at least 70 Gy (rectal V70). The increase in fractional doses raises concerns regarding greater rectal toxicity, but longer-term results are needed to clarify this issue. Approaches to minimize rectal radiation doses and thereby reduce treatment-related morbidity have become increasingly important in the management of prostate cancer.

Proton therapy has been used as a strategy to minimize radiation dose to adjacent structures including the rectum. Prior reports indicate that rectal volumes receiving 10 to 80 Gy are significantly lower with proton therapy (eg, V70 = 7.9%) than with intensity-modulated (photon) radiation therapy (IMRT) (eg, V70 = 14%), although others have questioned whether proton therapy alone is sufficient to reduce the rectal volume receiving high radiation doses. The 2 primary proton modalities, passive scattering proton therapy (PSPT) and intensity-modulated proton therapy (IMPT), have been compared for their relative ability to spare the rectum. An emerging approach aimed at further rectal sparing involves the use of biodegradable hydrogel spacers that physically displace the prostate from the rectal wall during treatment. In one randomized trial, use of such a spacer led to a relative reduction in mean rectal V70 of 74%. These studies suggest that significant dosimetric benefit requires at least 7- to 15-mm separation between the prostate and rectal wall.

The purpose of this study is to determine the effect of a biodegradable, injectable hydrogel spacer on rectal dose in treatment plans for PSPT and IMPT for prostate cancer. We analyzed a variety of clinically relevant dosimetric parameters for both modalities in the presence and absence of these spacers, and we correlated the extent of displacement between the prostate and rectal wall (with the spacer in place) with rectal V70 to determine the optimal amount of displacement in terms of reducing rectal dose in both modalities.

(A) : Dose-volume histogram for prostate, rectum, and seminal vesicles for representative patient ; (B) : isodose lines for PSPT without spacer (C) : PSPT with spacer (D) : IMPT without spacer (E) : IMPT with spacer . Normal tissues depicted with colorwash include prostate (blue), seminal vesicles (orange), and rectum (green). Abbreviations: IMPT, intensity-modulated proton therapy; PSPT, passive scattering proton therapy.

Conclusion: Use of biodegradable hydrogel spacers for prostate cancer treatment provides a significant reduction of radiation dose to the rectum with proton therapy. Significant reductions in rectal dose occurred in both PSPT and IMPT plans, with the greatest reduction for IMPT-with-spacer relative to PSPT alone. Prospective studies are ongoing to assess the clinical impact of reducing rectal dose with hydrogel spacers.

International Journal of Particle Therapy: Spring 2019, Vol. 5, No. 4, pp. 23-31.https://www.theijpt.org/doi/pdf/10.14338/IJPT-18-00041.1

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

Medulloblastoma is an excellent candidate for proton therapy

Medulloblastoma: optimizing care with a multidisciplinary approach, Thomas A, Noël G

(…) In the last decade, the use of proton therapy has rapidly increased as a result of its capacity to better spare organs at risk by eliminating the exit radiation dose due to the characteristic dose distribution of the proton beam modeled by the Bragg peak. This treatment is particularly relevant in childhood malignancies since it offers the promise of decreased late radiation-related morbidities, especially second neoplasms. Medulloblastoma, specifically due to a particularly large irradiation field, is an excellent candidate for proton therapy. Indeed, protons eliminate the dose of exit radiation into the chest, abdomen, and pelvis as well as the cochlea, pituitary, and hypothalamus of children after CSI. Translation into quality of life (QoL) has been studied in a prospective trial. QoL scores were found to improve over time after proton CSI, and after 5 years, children-reported scores were statistically similar to those of healthy children, but the parent-reported scores remained statistically lower than those reported by the parents of healthy children. To evaluate the superiority of proton therapy in medulloblastoma treatment with an evidence-based approach, a review recently compared the outcomes of pediatric medulloblastoma patients between proton- and photon-mediated CSI, and revealed the advantage of proton therapy in organs at risk sparing, normal organ dysfunction, and secondary malignancy risks compared to various (mostly 3D-CRT) photon techniques. A comparison of target coverage between both radiation modalities showed either similar or better results with proton therapy. However, proton therapy is a modern radiation modality, and the earliest study considered in this review was from 1997. For that reason, data regarding late toxicity after proton therapy are not available. On the other hand, we cannot ignore that second neoplasms after CSI mostly occur in the neuraxis, and this effect cannot be avoided with any irradiation modality as long as CSI is performed. The only way to determine with any certainty whether proton therapy should be developed as a standard of care for CSI would be through a prospective randomized controlled trial comparing both treatment modalities. Such a trial should include cost-effectiveness analysis since proton therapy is undoubtedly associated with higher initial infrastructural costs than those for photon therapy. At the present time, proton therapy remains a limited resource, and socioeconomic factors impact access to this treatment. (…)

https://www.dovepress.com/medulloblastoma-optimizing-care-with-a-multidisciplinary-approach-peer-reviewed-article-JMDH

Surgery and proton beam therapy for mediastinal extraskeletal osteosarcoma

Nahoko Shimizu MD, Yugo Tanaka MD, PhD Yusuke Demizu MD, PhD, Tomoaki Okimoto MD, PhD, Yoshimasa Maniwa MD, PhD

Extraskeletal osteosarcoma (ESOS) arising from the mediastinum is a rare malignant tumor and associated with a poor prognosis. We present the case of a 73-year-old man with a hoarseness. Imaging studies revealed a large calcified tumor of the median mediastinum. Surgery was performed, but complete resection was impossible and about two-thirds of the tumor was excised. The tumor was pathologically diagnosed as ESOS. Proton beam therapy has been performed on the remaining lesion, and the patient is alive without tumor regrowth for 29 months. This is the first case of mediastinum ESOS successfully treated with surgery and postoperative proton therapy.

https://doi.org/10.1016/j.athoracsur.2019.03.075G