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

Proton Therapy is highly effective at treating numerous cancers and tumors.

Proton Therapy was pioneered in the United States more than 50 years ago. By the end of 2018 it had been used to treat more than 170,000 patients.

Over the past decade, Proton Therapy has emerged as the most effective treatment method for a variety of cancers. Because it is a more accurate method for delivering radiation to the site of a tumor, proton therapy allows doctors to use a higher dose of radiation, without the risk of damage to surrounding healthy tissue and organs. Proton therapy patients experience relatively few harmful side effects and are able to maintain a high quality of life during and after treatment.

Proton Therapy is associated with favorable outcomes for intelligence and processing speed

Improved neuropsychological outcomes following proton therapy relative to x-ray therapy for pediatric brain tumor patients

Jeffrey P Gross, Stephanie Powell, Frank Zelko, William Hartsell, Stewart Goldman, Jason Fangusaro, Rishi R Lulla, Natasha Pillay Smiley, John Han-Chih Chang, Vinai Gondi, Neuro-Oncology, , noz070, https://doi.org/10.1093/neuonc/noz070

Abstract

Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent x-ray radiotherapy (XRT) versus proton radiotherapy (PRT).Methods

Pediatric patients who underwent either XRT or PRT and received post-treatment age-appropriate neuropsychological evaluation including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time.Results

Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%) or posterior fossa (53.6%) compartments received radiation and had post-treatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated socioeconomic status and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs. 2.6 years, p<0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (=10.6, p=0.048) and processing speed (=14.4, p=0.007) relative to XRT, with trend toward higher verbal IQ (=9.9, p=0.06) and general adaptive functioning (=11.4, p=0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ, (p=0.01) and IQ (p=0.04) following PRT, with trend toward improved processing speed (p=0.09).Conclusions

PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Treatment of inoperable NSCLC with IMPT and concurrent chemotherapy achieves excellent disease control with tolerable toxicity.

Clinical outcomes after intensity-modulated proton therapy with concurrent chemotherapy for inoperable non-small cell lung cancer

Adnan Elhammali, Pierre Blanchard, Alison Yoder, Zhongxing Liao, Xiadong Zhang, X. Ronald Zhu, Pamela K. Allen, Melenda Jeter, James Welsh, Quynh-Nhu Nguyen

Highlights

Intensity modulated proton therapy is a highly conformal treatment option.•

Treatment of inoperable NSCLC with IMPT offers excellent disease local control.•

Treatment was well tolerated with no grade 4 or 5 toxicity.

Abstract

Background & purpose

We report disease control, survival, and toxicity in patients with advanced inoperable non-small cell lung cancer (NSCLC) receiving concurrent chemotherapy and intensity-modulated proton therapy (IMPT) at a single institution.

Material and methods

All patients were treated with IMPT with concurrent chemotherapy. Endpoints assessed were local, regional, and distant control, disease-free survival (DFS), and overall survival (OS).

Results

Fifty-one patients were enrolled with a median follow-up time of 23.0 months; 39 (76%) were treated with a simultaneous integrated boost to the gross tumor volume (GTV). The median GTV dose was 67.3 CGE and the median CTV dose was 60.0 CGE. Median OS and DFS times were 33.9 months and 12.6 months. The 3-year local control rate was 78.3%. Treatment was well tolerated, with a grade 3 toxicity rate of 18% (9 events: 4 esophagitis, 3 dermatitis, 1 esophageal stricture, and 1 fatigue) and no grade 4 or 5 toxicity. The most common grade 2 toxic effects were esophagitis (22 [43%]), dermatitis (16 [31%]), pain (15 [29%]), and fatigue (14 [27%]).

Conclusions

Treatment of inoperable NSCLC with IMPT and concurrent chemotherapy achieves excellent disease control with tolerable toxicity.

https://www.sciencedirect.com/science/article/pii/S0167814019301513

Consider Proton Therapy to limit those side effects and to improve Quality of Life

Proton therapy can provide a better quality of life for cancer patients. It can spare them the grueling post-treatment complications described in article below that are common with conventional Radiation Therapy..

Understanding the Management of Chronic AEs After Radiation Therapy

“Treatment techniques and comorbidities have a significant impact on the severity of chronic side effects,” said Haynes-Lewis, a nurse practitioner at Montefiore Einstein Center for Cancer Care. “Nurses should work with the patients to develop a plan to manage chronic side effects that optimize quality of life.”

To start, she added, knowing the difference between late AEs (those that occur or begin after therapy is completed and may occur months to year post-treatment) and long-term AEs (prolonged effects that begin during treatment and continue beyond the end of treatment) is important.

In her presentation, Haynes-Lewis focused on the management of chronic late side effects among patients with cancer.

Central Nervous System

Disease sites under this category can include the brain and spinal cord, from which the tissue are late reacting. Therefore, these changes are found, not in the clinic, but through imaging.

AEs of the central nervous system include increased atherosclerosis of the blood vessels in the brain, increased incidence of secondary brain tumors, radiation necrosis, cognitive decline, hormonal deficits, vision changes, hearing loss, and radiation myopathy.

“This is where nurses come in because we really need to educate, educate, educate the patients and their families,” Haynes-Lewis said. “We need to talk to them about the symptoms of stroke, incidents of what it looked like if you had a tumor – headaches, changes in vision, changes in gait, changes in mental status – those are all things that we need to talk to the patient about. A lot of times I tell them, maybe you just don’t feel right because there aren’t any words. And if they don’t feel right, I tell them to call their provider. Sometimes that is what happens.”

AEs associated with the central nervous system are often treated with steroids, bevacizumab (Avastin), hyperbaric oxygen therapy, surgical resection, memantine, donepezil (Aricept), cognitive rehabilitation, cochlear implants, hormonal replacement, and pentoxifylline.

Head and Neck

These AEs can occur in the nasopharynx, oral cavity, salivary glands, or neck. They include xerostomia, dysgeusia, fibrosis, lymphedema, dysphagia, dental caries, osteoradionecrosis, hearing loss, neuropathy, and changes in voice quality.

“These side effects affect every part of your life and your quality of life,” Haynes-Lewis said.

Management of these AEs can include acupuncture and massage, therapy (physical therapy, decongestive therapy, swallowing rehabilitation), and medications such as pentoxifylline, vitamin E, analgesics, saliva substitutes and stimulants, conservative debridement, hyperbaric oxygen, surgical resection and reconstruction, hearing aids, tympanostomy and aspiration, myringotomy and grommet insertion, voice therapy, and injection larynoplasty.

“You need to help (the patients) by just putting 2 and 2 together,” Haynes-Lewis said. “If you have a dry mouth, what does that do? It can affect your teeth, so we need to make sure (the patient) is seeing the dentist, that they are doing good oral hygiene and that they understand what that is and how to do it.”

Chest

AEs of the chest can occur in the breast, lung, mediastinal or axillary adenopathy, or esophagus. In this area of the body, risk factors for chronic AEs include age, gender, treatment techniques, concurrent chemotherapy, lung disease, history of smoking, and poor performance status.

Chest AEs from radiation include exacerbation or worsening of underlying comorbid lung disease, lung fibrosis, chest wall fibrosis, esophageal stricture, telangiectasias, pain, lymphedema, brachial plexopathy, and cardiotoxicity. These can be managed with dietary and behavioral modifications, pulmonary rehabilitation and physical therapy, esophageal dilation, and medications such as steroids, anti-inflammatories, gabapentin, pentoxifylline, vitamin E, prokinetic agents, and oxygen therapy.

Abdomen

In disease sites of the abdomen (gastric, liver, pancreas, colon, stomach, and small bowel), radiation therapy is commonly used in neoadjuvant and adjuvant treatment, as well as effective palliation for pain, bleeding, and obstruction.

AEs include dysmotility, stricture, fistula, obstruction, ulceration or perforation, and bleeding. To manage these, Haynes-Lewis recommended for dietary modifications; medications like analgesics, enzyme supplementation, anti-diarrheal, antiemetics, and proton pump inhibitors; endoscopic dilation; percutaneous endoscopic gastrostomy tube; and surgical intervention.

Pelvis

Sites for these AEs can include the prostate, bladder, cervix, ovaries, and colon, for which chronic toxicity can be correlated with the volume of radiation received.

These AEs–including diarrhea, hemorrhoids, proctitis, leakage of fecal incontinence, fistula or stricture, and obstruction–can be managed with dietary modifications; bowel rest; medications such as anti-diarrheal, sucralfate enemas, steroid suppositories and creams, and topical lidocaine; endoscopic interventions; hyperbaric oxygen therapy; and surgical resection.

Skin and Extremities

These AEs can include telangiectasia, chronic dermatitis, pigmentation changes, atrophy, fibrosis, ulceration, bone fractures, alopecia, and edema. In addition, they are often managed with antihistamines, colloidal oatmeal treatments, aloe, massages, physical therapy, and wound care.

In addition, Haynes-Lewis noted that global chronic AEs, such as fatigue, depression, insomnia, pain, anxiety, and post-traumatic stress disorder, exist across all cancer types, adding that these can be managed with medications, exercise, energy conservation, mind-body techniques, therapy, and referral to a survivorship program.

“Nurses should be at the forefront of chronic side effect management as part of survivorship care as the number of cancer survivors continue to increase,” she concluded.

https://www.oncnursingnews.com/conference-coverage/ons-2019/understanding-the-management-of-chronic-aes-after-radiation-therapy

Technical Prevention of Radiation-induced Cardiovascular Toxicity

WANG Xuanyi, YU Xiaoli

Radiotherapy has been an important component of cancer treatment. In the malignancy with long survival, radiation-induced cardiovascular toxicity significantly jeopardize patients’ outcome. Despite that its pathophysiological mechanism is not clear yet, many studies have confirmed the positive correlation between cardiovascular involvement dose, irradiated volume and radiation-induced cardiotoxicity. Therefore, reducing cardiovascular involvement dose as well as irradiated volume is the key to cardiac sparing techniques in radiotherapy. Cardiac sparing techniques includes: (1) methods that reduce radiation fields and dose; (2) methods that increase the distance between heart and irradiated fields; (3) new techniques such as intensity modulated radiotherapy and proton therapy. Although researches in dosimetry have showed that cardiac sparing techniques could lower cardiovascular involvement dose and irradiated volume, further validation is needed for curative effect.

http://www.zlfzyj.com/EN/10.3971/j.issn.1000-8578.2018.18.0887

Patient outcome of pencil beam-scanning proton therapy in Head and Neck adenoid cystic carcinoma

M. Pelak, M. Walser, B. Bachtiary, A. Bolsi, J. Hrbacek, A. Lomax, U. Kliebsch1, A. Pica, D.C. Weber

“Proton beam therapy using PBS is an effective and safe way of delivering definitive and adjuvant irradiation in patients with Adenoid Cystic Carcinoma (ACC) of the head and neck region. Most ACC patients that progressed after treatment failed distantly.”

https://lnkd.in/dEA3_rm

Advances in Neuro-oncology

Proton Therapy for Children and Adults

Proton therapy has grown in prominence in recent years as another radiotherapy technique that spares healthy tissue. Unlike photons, which travel all the way through a target and come out the other side, protons can be programmed to stop inside the target, delivering the entire dose to a tumor.

Proton therapy particularly offers attractive benefits for pediatric cancer patients, as they are susceptible to more long-term effects of radiation. Gondi and colleagues at Northwestern presented another study at the 2018 American Society for Radiation Oncology (ASTRO) meeting comparing neurocognitive effects of proton versus photon therapy in 125 children with brain tumors. The median age at diagnosis was 7 years old, and the median time from treatment to last assessment was four years. According to Gondi, the children treated with proton therapy scored higher post-treatment in full-scale IQ, processing speed and parent-reported practical functions.

Proton therapy also offers opportunities for treating adults with brain tumors, particularly gliomas, one of the most common types of primary brain tumors. In particular, Gondi is interested in low-grade gliomas, a slow-growing tumor that can develop earlier in life. “The average age of someone with a low-grade glioma is actually 37 — that’s the prime of these young adult lives. Their cognitive function is so important. So we’re using proton therapy to try to treat that tumor, avoid as much unnecessary radiation dose to normal brain tissue, and see if we can’t help preserve that cognitive function,” he said.

“It’s about that survivorship and how we can optimize that survivorship,” he added.

https://www.itnonline.com/article/advances-neuro-oncology