Proton therapy for the treatment of cancer in children and adults

Half of all cancer patients receive radiotherapy at some point during their treatment. Radiotherapy aims to damage the cancer cells whilst preserving adjacent healthy tissue and organs in order to cure, shrink or control the tumor, or to prevent tumor recurrence. Proton radiotherapy can be delivered with higher precision compared to conventional photon radiotherapy, which may lead to decreased toxicity in cancer patients.

Reading time approx. 21 minutes Published: June 29, 2021 Publication type:

SBU Enquiry Service

Consists of structured literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. We assess the risk of bias in systematic reviews and when needed also quality and transferability of results in health economic studies. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed.

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Published: June 29, 2021 Report no: ut202117 Registration no: SBU 2020/936

Table 1. Systematic reviews with low/medium risk of bias.
3D-CRT = Three-dimensional conformal radiation therapy; bRFS = Biochemical relapse-free survival; CSS = Cause-specific survival; CNS = Central nervous system; DFS = Disease-free survival; FSIQ =Full scale intelligence quotient; GI = Gastrointestinal; GU = Genitourinary; HART = Hyper-fractionated accelerated radiotherapy; HCC = Hepatocellular carcinoma; HTA = Health technology assessment; IMRT = Intensity modulated radiation therapy; OS = Overall survival; PFS = Progression-free survival; QoL = Quality of life; RCT = Randomised controlled trial; RFS = Relapse-free survival; RILD = Radiation-induced liver disease; RoB = Risk of Bias; SOE = Strength of Evidence; SRS = stereotactic radiosurgery; XRT = X-ray radiation therapy
Included studies
Skelly et al, 2019 Washington state Health Care Authority, USA Proton Beam Therapy [1] Medium risk of bias Study type: HTA report
215 Original studies 4 HTA reports 13 Systematic reviews Adult (n=155) 2 RCT 1 Quasi-RCT 33 Comparative cohorts 115 Case series 4 Economics Paediatric (n=56) 13 Comparative cohorts 41 Case series 2 Economics Contextual studies (n=4) Summarised HTA reports (n=4) 2 Adults and paediatrics 2 Adults only Summarised systematic reviews (n=13) 11 Adults 2 Paediatric	Population: Adults and children undergoing treatment of primary or recurrent cancer: Bone cancer, brain, spinal, and paraspinal tumours, breast cancer, oesophageal cancer, gastrointestinal cancer, gynaecologic cancer, head and neck cancer, liver cancer, lung cancer, lymphomas, ocular tumours, paediatric cancers, prostate cancer, sarcomas, seminoma, thymoma, other cancers, and noncancerous conditions (arteriovenous malformations, haemangiomas, other benign tumours)	Intervention: Comparative impact of proton beam therapy (PBT) treatment with curative intent on survival, disease progression, health-related quality of life, and other patient outcomes, versus radiation therapy alternatives and other cancer-specific treatment options (e.g., surgery, chemotherapy)
Results
Summary of results, paediatric tumours: Paediatric brain tumours PBT vs other RT: Benefits in terms of OS, PFS and tumour recurrence generally similar. Some differences may be clinically important. (4 comparative studies, low strength of evidence, SOE). PBT vs other RT: Toxicities and harms; hypothyroidism less common with PBT (low SOE). Many other toxicities (incl. other endocrine-related toxicities) tended to be less frequent with PBT. Some differences may be clinically important. (Low SOE). One retrospective cohort reported no difference between PBT and photon therapy for FSIQ scores. (Low SOE for all outcomes). None of the included studies evaluated differential effectiveness or safety. Other paediatric tumours Evidence for effectiveness and safety was considered to be insufficient for all other paediatric tumours. No studies identified on differential effectiveness or safety. Key points across adult tumour categories/conditions: Bladder cancer Insufficient evidence (1 case series) to evaluate the effectiveness or safety of PBT. No studies identified that evaluated salvage therapy, differential effectiveness and safety or cost-effectiveness. Bone tumours Insufficient evidence (7 case series) to evaluate the effectiveness or safety of PBT. No studies identified that evaluated salvage therapy, differential effectiveness and safety. Brain, spinal, paraspinal tumours Inconsistent results for OS and PFS for PBT (curative intent) for different types of brain tumours (2 retrospective case-matched cohorts): 1) photon RT + PBT boost vs photon RT alone, high-grade glioblastoma 2) PBT vs photon RT, primarily high-grade glioma (Low SOE for both comparisons) In metastatic CNS disease, salvage PBT vs photon RT: No statistically significant difference in probability of 6-month OS or CNS relapse. (1 small retrospective cohort study, insufficient SOE) No statistical difference seen between groups in frequency of acute grade 3 toxicity (2 studies) or of radiation necrosis (1 study, curative intent) or severe CNS toxicity (1 study, salvage therapy) over the late term. (Low SOE for curative intent; insufficient SOE for salvage therapy) No studies identified on differential effectiveness and safety. Breast cancer PBT vs photon with/without electron boost therapy: No statistical difference in the probability of OS at 5 years. (1 retrospective comparative database study, low SOE) No studies identified on salvage therapy or differential effectiveness and safety. Oesophageal tumours PBT vs IMRT or 3D-CRT: OS at 1 year similar between groups; probabilities of OS and PFS/DFS over 1 to 5 years follow-up greater with PBT vs IMRT or 3D-CRT (2 studies). Statistical significance achieved only in the largest study. (Low SOE) PBT vs photon RT (IMRT, 3D-CRT, XRT: No statistically significant differences in mortality. (2 studies, low SOE for the large, higher quality study; insufficient SOE for the small, poorer-quality study) PBT vs 3D-CRT or XRT: Except for GI events, statistically less treatment-related toxicity with PBT (i.e., pulmonary, cardiac, and wound events; grades ≥2 or not specified). (3 studies, low SOE for all) No studies identified that evaluated salvage therapy, differential effectiveness and safety. Gastrointestinal (pancreatic) tumours PBT vs HART: No statistically significant differences in probability of 1- to 3-year OS, disease control/local progression or metastases, or frequency of grade ≥3 radiation-related haemato-logical/non-haematological toxicities; clinical importance of differences is unclear (1 small retrospective study, curative intent, insufficient SOE). No studies identified that evaluated salvage therapy, differential effectiveness and safety. Head and Neck tumours (including skull-base) PBT vs IMRT: No statistical differences in probabilities of 1- to 3-year OS, PFS (1 case-matched study, primary oropharyngeal cancer), incidence of all-cause mortality over a median 24 months (1 small study, primary nasopharyngeal cancer), and 1-year OS (1 small study, primary or metastatic salivary gland cancer). Clinical significance of differences is unknown (low SOE for primary oropharyngeal and nasopharyngeal cancer; insufficient SOE for primary or metastatic salivary gland cancer). PBT vs IMRT: No statistically significant differences in frequency of grade ≥3 acute or late toxicities (3 studies) or incidence of ED visits/unplanned hospitalisations (1 study) (low SOE based on largest, best quality study). PBT vs IMRT: No statistical difference in the incidence of osteoradionecrosis after 6 months in treatment of oropharyngeal cancer. (1 study, insufficient SOE) Gastrostomy tube dependence tended to be lower with PBT (5 retrospective comparative cohort studies; 2 on primary oropharyngeal, 1 each of primary nasopharyngeal; primary nasopharyngeal or paranasal sinus; and primary or meta-static salivary gland cancer). Adjusted estimates from largest study not statistically significant, while smaller studies reported statistically significant differences. Large confidence interval in smallest study suggests instability of effect estimate. Clinical significance of differences is unclear. No comparative studies identified on salvage therapy or differential effectiveness and safety. Liver tumours PBT vs IMRT: OS statistically higher after PBT (1 study) one retrospective cohort study of adult patients with unresectable HCC but there was no difference in local and regional control between groups. (Low SOE) Lower risk of non-classic RILD (1 retrospective cohort study, low SOE) Lower risk of death due to liver failure (Insufficient SOE) No comparative studies identified on salvage therapy or differential effectiveness and safety. Lungs PBT vs IMRT: No statistically significant differences seen in probability of OS at any timepoint up to 5 years, or in the cumulative incidence of local failure in patients with non-small cell lung cancer being treated with curative intent. (1 fair quality RCT, moderate SOE) Findings from 4 retrospective comparative cohort studies were consistent with those of the RCT. No statistical differences seen in the frequency of grade ≥3 radiation pneumonitis at any timepoint up to 5 years. (1 fair-quality RCT, moderate SOE) No statistical difference regarding grade ≥3 toxicities (radiation pneumonitis, radiation esophagitis, radiation dermatitis). Clinical importance of differences unknown. (2 retrospective cohort studies, insufficient SOE). One comparative study on salvage PBT with no survival or safety data, no studies identified on differential effectiveness and safety. Lymphoma Insufficient evidence (3 case series) to evaluate effectiveness and safety of PBT with curative intent in adults (primarily) with Hodgkin or non-Hodgkin lymphoma. No studies identified on salvage therapy, differential effectiveness and safety. Ocular tumours PBT vs brachytherapy or SRS (curative intent): No statistically significant differences in OS at 2 years and mortality at 3 years. At 5 years statistically higher risk of mortality with PBT vs brachytherapy in the larger, higher quality study. (2 retrospective cohort studies, low SOE) No statistical differences in frequency of adverse events (radiation retinopathy, enucleation, rubeosis of the iris, neovascular glaucoma, rubeotic glaucoma) over 3 years. (2 retrospective comparative cohort studies, low SOE) PBT vs brachytherapy: Statistically lower frequency of local recurrence over 10 years. (1 retrospective comparative cohort study, low SOE) PBT vs SRS: No difference in local recurrence at 3 years. (1 poor quality study, insufficient SOE) Optic neuropathy statistically lower following PBT (1 study). No comparative studies identified on salvage therapy or differential effectiveness and safety. Prostate tumours Photon RT + PBT boost vs photon RT only: No statistically significant differences in probability of 5- and 10-year OS and bRFS. (1 quasi-RCT, low SOE) Probability of acute and late grade 2 GI toxicity, but not GU toxicity, significantly lower after photon RT + PBT boost. (1 quasi-RCT, low SOE) No statistically significant differences for grade 3 or 4 toxicities. PBT vs IMRT: Results on acute and late GU toxicity differed. No statistical difference between groups (2 retrospective cohort studies) and lower cumulative incidences (1 large database cohort study) with PBT (including erectile dysfunction). Differences between groups were small and clinical significance is unknown. (Low SOE for all) No studies identified on PBT for salvage therapy, differential effectiveness and safety.
Authors' conclusion: “The overall quality of the available evidence base was considered poor. Comparative evidence for this report is primarily from retrospective, non-randomized (observational) studies which were considered to be at moderately high risk of bias except where noted in the detailed description of results. […] In most instances, treatment groups were formed based on historical changes in methods of radiation therapy delivery, i.e. more conventional photon radiation therapy, including 3DCRT, was delivered to patients at a time prior to a switch to PBT as it became more the available. […] Differences between treatment groups in patient characteristics, presentation, tumour stage, comorbidities, prior or concurrent treatments and surgical factors were noted in most studies. Although many studies evaluated possible confounding by such factors, there is the possibility of residual confounding or other biases that could influence results.”
Ontario Health, 2021 Canada Proton Beam Therapy for Cancer in Children and Adults: A Health Technology Assessment [2] Study type: HTA report
Includes: One systematic review [10] (reporting on 215 publications on proton beam therapy in children and adults across 19 tumour categories/conditions). No clinical trials included.	P: Children and adults with cancer I: Proton beam therapy C: Photon therapy O: OS, PFS, RFS, acute and late toxicity	RoB-assessment Medium RoB. Some shortcomings in independent assessment of identified studies.
Vlayen et al, 2019 The Belgian Health Care Knowledge Centre (KCE), Belgium Proton beam therapy in adults – a systematic review [3] Study type: HTA report
Includes: 11 systematic reviews/HTA reports 6 controlled studies 22 non-controlled studies	P: Adults with certain malign conditions I: Proton beam therapy C: Photon therapy O: OS, PFS, RFS, adverse effects, complications, secondary tumours, QoL, LTC etc	RoB-assessment Medium RoB. Some shortcomings in independent assessment of identified studies.
Kim et al, 2017 Canadian Agency for Drugs and Technologies in Health (CADTH), Canada Proton beam therapy for the treatment of cancer in children and adults: a health technology assessment [4] Study type: HTA report
Includes:: 9 systematic reviews	P: Children and adults with malign conditions, except skin cancer I: Proton beam therapy C: Other types of radiation therapy O: OS, PFS, RFS, acute and late toxicity, metastasis, secondary tumours etc	RoB-assessment Medium RoB.
Leroy et al, 2015 The Belgian Health Care Knowledge Centre (KCE), Belgium Hadron therapy in children – an update of the scientific evidence for 15 paediatric cancers. [5] Study type: HTA report
Includes: 2 controlled studies 19 non-controlled studies	P: Children with cancer (16 different malign conditions) I: Proton beam therapy or carbon ion therapy C: Photon beam therapy (surgery and chemotherapy also included in this review) O: Clinical effects, adverse events, complications, secondary tumours	RoB assessment Medium RoB. Some shortcomings in independent assessment of identified studies.
Ratko et al, 2014, The Agency for Healthcare Research and Quality's (AHRQ), USA Radiotherapy Treatments for Head and Neck Cancer [6] Study type: HTA report
Includes: No comparative studies on proton beam therapy were included.	P: Patients with head and neck cancer I: Photon beam therapy (3DCRT, IMRT, SBRT) and proton beam therapy C: All therapies were compared with each other, as part of a continuum of treatment O: OS, CSS, LTC, TTR, QoL, adverse events etc	RoB assessment Low RoB

References

Skelly AC, Brodt ED, Schwartz N, Ferguson A, JR., Kantner S. Proton Beam Therapy–Re-review. Final evidence report. Washington State Healthcare Authority - Health Technology Assessment Program (HTA); 2019. Available from: https://www.hca.wa.gov/assets/program/proton-beam-therapy-rr-final-report-20190418.pdf.
Proton beam therapy for cancer. ["Ontario Health", "130 Bloor Street West, 10th Floor", "OH-HQO_hta-reg@ontariohealth.ca", "Nancy Sikich", "Canada", "Ontario"] Canada: Ontario Health; 2020 2020.
Vlayen J, García Fernández Ll, Boterberg T, San Miguel L. Proton beam therapy in adults – a systematic review. Health Technology Assessment (HTA) Brussels: Belgian Health Care Knowledge Centre (KCE). 2019. KCE Reports 307. D/2019/10.273/10. Available from: https://kce.fgov.be/sites/default/files/atoms/files/KCE_307_Proton_beam_therapy_adults_Report.pdf.
CADTH. Proton beam therapy for the treatment of cancer in children and adults: a health technology assessment. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2017 Aug. (CADTH health technology assessment; no.145). Available from: https://www.cadth.ca/sites/default/files/pdf/HT0017_PBT_Report.pdf.
Leroy R, Benahmed N, Hulstaert F, Mambourg F, Fairon N, Van Eycken L, De Ruysscher D. Hadron therapy in children – an update of the scientific evidence for 15 paediatric cancers. Health Technology Assessment (HTA) Brussels: Belgian Health Care Knowledge Centre (KCE). 2015. KCE Reports 235. D/2015/10.273/04. Available from: https://kce.fgov.be/sites/default/files/atoms/files/KCE_235_Hadron%20Therapy_Report.pdf.
Ratko TA, Douglas GW, de Souza JA, Belinson SE, Aronson N. Radiotherapy Treatments for Head and Neck Cancer Update. Comparative Effectiveness Review No. 144. (Prepared by Blue Cross and Blue Shield Association Evidence-based Practice Center under Contract No. 290-2007-10058.) AHRQ Publication No. 15-EHC001-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014. Available from: https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/head-neck-cancer-update_research.pdf.

Literature search

Medline via OVID April 21, 2021

Proton therapy

	Search terms	Items found
The search result, usually found at the end of the documentation, forms the list of abstracts. [MeSH] = Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy; [MeSH:NoExp] = Does not include terms found below this term in the MeSH hierarchy; [MAJR] = MeSH Major Topic; [TIAB] = Title or abstract; [TI] = Title; [AU] = Author; [TW] = Text Word; Systematic[SB] = Filter for retrieving systematic reviews; * = Truncation
Intervention:
1.	exp Proton Therapy/	4,021
2.	exp Protons/ and (beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*).ti,ab,kf,kw,hw	3,948
3.	Protons/ae,tu	313
4.	(proton* and (beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*)).ti,kf,kw	4,758
5.	(proton* adj5 (beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*)).ab	6,452
6.	proton therap*.ti,ab,kf,kw	3,636
7.	protontherap*.ti,ab,kf,kw	111
8.	((particle* or hadron) and (beam or minibeam* or radiation* or irradiation* or radiotherap* or chemoradiation* or chemoradiotherap* or therap*)).ti,kf,kw	3,694
9.	((particle* or hadron) adj3 (beam or minibeam* or radiation* or irradiation* or radiotherap* or chemoradiation* or chemoradiotherap* or therap*)).ab	3,996
10.	(particletherap* or hadrontherap*).ti,ab,kf,kw	192
11.	(proton* and therap*).ti,kf,kw	4,746
12.	(proton* adj3 therap*).ab	5,453
13.	(PBT or PBRT).ti,ab,kf,kw	1880
14.	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13	20,838
NOT including:
15.	(proton? adj3 pump).tw	18,278
16.	ion? channel?.mp	81,397
17.	exp ion pumps/	186,576
18.	exp ion channels/	247,609
19.	15 or 16 or 17 or 18	447,120
Combined sets:
20.	14 not 19	18,726
Study types:
21.	exp systematic review/ or Cochrane library.mp. or exp meta analysis/	232,089
22.	((systematic* adj3 review) or meta analy or metaanaly*).ab,ti,kw	324,958
23.	21 or 22	353,783
Final	20 AND 23	182

Cochrane Library via Wiley April 21, 2021

Proton therapy

	Search terms	Items found
The search result, usually found at the end of the documentation, forms the list of abstracts. au = Author; MeSH = Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy; this term only = Does not include terms found below this term in the MeSH hierarchy; :ti = Title; :ab = Abstract; :kw = Keyword; * = Truncation; “ “ = Citation Marks; searches for an exact phrase CDSR = Cochrane Database of Systematic Review; CENTRAL = Cochrane Central Register of Controlled Trials, “trials”; CRM = Method Studies; DARE = Database Abstracts of Reviews of Effects, “other reviews”; EED = Economic Evaluations; HTA = Health Technology Assessments
Intervention:
1.	MeSH descriptor: [Proton Therapy] explode all trees	44
2.	MeSH descriptor: [Protons] explode all trees	106
3.	(beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*):ti,ab,kw	54,449
4.	2 AND 3	24
5.	MeSH descriptor: [Protons] explode all trees and with qualifier(s): [adverse effects - AE]	8
6.	(proton* and (beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*)):ti	228
7.	(proton* NEAR/5 (beam* or minibeam* or radiation* or irradiation* or radiotherap* or radio-therap* or chemoradiation* or chemoradiotherap*)):ab	287
8.	(“proton therap” or protontherap):ti,ab,kw	4
9.	((particle* or hadron) and (beam or minibeam* or radiation* or irradiation* or radiotherap* or chemoradiation* or chemoradiotherap* or therap*)):ti	71
10.	((particle* or hadron) NEAR/3 (beam or minibeam* or radiation* or irradiation* or radiotherap* or chemoradiation* or chemoradiotherap* or therap*)):ab	91
11.	(proton* and therap*):ti	475
12.	(proton* NEAR/3 therap*):ab	553
13.	(PBT or PBRT):ti,ab,kw	177
14.	1 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13	1,189
NOT included:
15.	(proton* NEAR/3 pump):ti,ab,kw	4,083
16.	("ion* channel*"):ti,ab,kw	187
17.	MeSH descriptor: [Ion Pumps] explode all trees	1,379
18.	MeSH descriptor: [Ion Channels] explode all trees	1,286
19.	15 or 16 or 17 or 18	6,740
Combined sets:
20.	14 not 19	693
Limits:
21.	20 [in Cochrane Reviews]	3
Final		3

Embase via embase.com April 21, 2021

Proton therapy

	Search terms	Items found
/de = Term from the EMTREE controlled vocabulary; /exp = Includes terms found below this term in the EMTREE hierarchy; /mj = Major Topic; :ab = Abstract; :au = Author; :ti = Article Title; :ti,ab = Title or abstract; * = Truncation; ’ ’ = Citation Marks; searches for an exact phrase
Intervention:
1.	'proton therapy'/exp	9,259
2.	'proton'/exp AND (beam:ti,ab,kw OR minibeam:ti,ab,kw OR radiation:ti,ab,kw OR irradiation:ti,ab,kw OR radiotherap:ti,ab,kw OR 'radio therap':ti,ab,kw OR chemoradiation:ti,ab,kw OR chemoradiotherap:ti,ab,kw)	7,092
3.	proton:ti,df,dn AND (beam:ti,df,dn OR minibeam:ti,df,dn OR radiation:ti,df,dn OR irradiation:ti,df,dn OR radiotherap:ti,df,dn OR 'radio therap':ti,df,dn OR chemoradiation:ti,df,dn OR chemoradiotherap*:ti,df,dn)	5,760
4.	(proton* NEAR/5 (beam* OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR 'radio therap' OR chemoradiation OR chemoradiotherap*)):ab	10,006
5.	'proton therap':ti,ab,kw OR protontherap:ti,ab,kw	6,651
6.	(particle:ti,kw OR hadron:ti,kw) AND (beam:ti,kw OR minibeam:ti,kw OR radiation:ti,kw OR irradiation:ti,kw OR radiotherap:ti,kw OR chemoradiation:ti,kw OR chemoradiotherap:ti,kw OR therap:ti,kw)	4,884
7.	((particle* OR hadron) NEAR/3 (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap*)):ab	5,259
8.	particletherap:ti,ab,kw OR hadrontherap:ti,ab,kw	372
9.	proton:ti,kw AND therap:ti,kw	7,900
10.	(proton* NEAR/3 therap*):ab	9,438
11.	pbt:ti,ab,kw OR pbrt:ti,ab,kw	2,712
12.	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11	31,257
Limits:
13.	(proton* NEAR/3 pump):ti,ab,kw	30,943
14.	'ion* channel*':ti,ab,kw	56,891
15.	'ion pump'/exp	31
16.	'ion channel'/exp	255,400
17.	#13 OR #14 OR #15 OR #16	300,957
Combined sets:
18.	#12 NOT #17	27,613
Study types:
19.	'systematic review'/exp OR 'meta analysis'/exp OR 'cochrane library':ti,ab,kw	408,433
20.	(((systematic* NEAR/3 review):ab,ti,kw) OR meta:ab,ti,kw) AND analy:ab,ti,kw OR metaanaly*:ab,ti,kw	318,627
21.	#19 OR #20	490,660
Final	#18 AND #21	358

Epistemonikos via epistemonikos.org April 21, 2021

Proton therapy

	Search terms	Items found
The search result, usually found at the end of the documentation, forms the list of abstracts. AB = Abstract; AU = Author; DE = Term from the thesaurus; MM = Major Concept; TI = Title; TX = All Text. Performs a keyword search of all the database's searchable fields; ZC = Methodology Index; * = Truncation; “ “ = Citation Marks; searches for an exact phrase
Intervention:
1.	(title:((title:(Proton* AND (therap* OR beam* OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR radio-therap* OR chemoradiation* OR chemoradiotherap)) OR abstract:(Proton AND (therap* OR beam* OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR radio-therap* OR chemoradiation* OR chemoradiotherap))) OR (title:("proton therap" OR protontherap) OR abstract:("proton therap" OR protontherap)) OR (title:(((particle OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap))) OR abstract:(((particle OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap)))) OR (title:((particletherap OR hadrontherap)) OR abstract:((particletherap OR hadrontherap))) OR (title:((PBT OR PBRT)) OR abstract:((PBT OR PBRT)))) OR abstract:((title:(Proton AND (therap* OR beam* OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR radio-therap* OR chemoradiation* OR chemoradiotherap)) OR abstract:(Proton AND (therap* OR beam* OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR radio-therap* OR chemoradiation* OR chemoradiotherap))) OR (title:("proton therap" OR protontherap) OR abstract:("proton therap" OR protontherap)) OR (title:(((particle OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap))) OR abstract:(((particle OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap)))) OR (title:((particletherap OR hadrontherap)) OR abstract:((particletherap OR hadrontherap))) OR (title:((PBT OR PBRT)) OR abstract:((PBT OR PBRT))))) NOT (title:((proton AND pump) OR ("ion* (channel* OR pump)")) OR abstract:((proton AND pump) OR ("ion* (channel* OR pump*)")))	732
Limits:
	Systematic reviews
Final		281

INHTA via database.inahta.org May 12, 2021

Proton therapy

	Search terms	Items found
The search result, usually found at the end of the documentation, forms the list of abstracts. [mh] = Term from the Medline controlled vocabulary, including terms found below this term in the MeSH hierarchy; [Title] = Title; [abs] = Abstract; * = Truncation
Intervention:
1.	((Proton Therapy )[mh] OR (proton* OR protontherap* )[Title] OR (proton* OR protontherap* )[abs] OR (((particle* OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap)) )[Title] OR (((particle OR hadron) AND (beam OR minibeam* OR radiation* OR irradiation* OR radiotherap* OR chemoradiation* OR chemoradiotherap* OR therap)) )[abs] OR (particletherap OR hadrontherap* )[Title] OR (particletherap* OR hadrontherap* )[abs] OR (PBT OR PBRT )[Title] OR (PBT OR PBRT )[abs])	81
NOT including:
2.	("proton* pump") OR ("ion* channel*") OR (ion pumps)[mh] OR (ion channels)[mh]	28
Combined sets:
3.	1 not 2	54
Final		54

Page published June 29, 2021

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