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Implementation of meta-analysis approach, comparing conventional radiotherapy, and proton beam therapy treating head and neck cancer


1 Department of Oral Medicine and Radiology, CSMSS Dental College and Hospital, Aurangabad, Maharashtra, India
2 Department of Biotechnology, Dr. Rafiq Zakaria Campus, Maulana Azad College, Aurangabad, Maharashtra, India

Date of Submission13-Feb-2019
Date of Decision19-May-2019
Date of Acceptance14-Oct-2019
Date of Web Publication09-Jun-2020

Correspondence Address:
Firdous Shaikh,
CSMSS Dental College & Hospital, Kanchanwadi, Aurangabad, 431002, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_111_19

 > Abstract 


Introduction: Radiation therapy is commonly used in the treatment of head and neck cancer in both the definitive and postoperative settings. Proton therapy, due to its intrinsic physical properties, has the ability to reduce the integral dose delivered to the patients while maintaining highly conformal target coverage
Materials and Methods:.A literature search was performed on scientific databases, and Preferred Reporting Items for Meta-Analyses guidelines were followed to compute results. Only original studies were selected. Selected studies were used to extract some proposed data for comparison, dosimetry, site, complications, and survival.
Results: Proton beam therapy technology can be used against the conventional radiotherapy and shows satisfactory results. Yet conventional therapy is not less advantageous considering the amount of work available for any cross interpretations.
Conclusion: Comparative preplanning could be beneficial considering multiple therapies for ruling out the best treatment outcomes that could be expected.

Keywords: Conventional radiation therapy, meta-analysis, proton beam therapy, proton therapy, radiotherapy



How to cite this URL:
Shaikh F, Sodhi SK, Kale LM, Talib YA, Saleem HM. Implementation of meta-analysis approach, comparing conventional radiotherapy, and proton beam therapy treating head and neck cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Sep 19]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=286246




 > Introduction Top


With the discovery of Roentgen rays in 1895, the field of medicine was revolutionized considering diagnosis and therapeutics. Radiation therapy is a well-established option for the management of head and neck tumors.[1] Radiotherapy is based on the basic principle that rapidly proliferating cells are more sensitive to ionizing radiation compared to normal cells. Ionizing radiation deposits energy that injures or destroys cells by causing DNA strands to break and cross-link.[2] The main objective of modern radiotherapy is to optimize radiation dose delivery in such a way that the tumor is sterilized while sparing nontarget normal tissues as much as possible.[3]

External beam radiotherapy of head and neck (H and N) (and thyroid) cancers is technically advanced and demanding of resources.[4] Innovations in the delivery of external beam radiation therapy, such as three-dimensional (3D) conformal radiation and intensity-modulated photon therapy (IMRT), have resulted in greatly improved cure rates and quality of life.[1] IMRT differs from 3D-conventional radiotherapy (3D-CRT); in that each X-ray beam is broken up into many “beamlets,” and the intensity of each beamlet can be adjusted individually.[5]

H and N radiotherapy with curative intent is based on the principle of irradiating all known tumor tissue with a margin up to a radical dose, which usually means a biological equivalent dose of at least 66–70 Gy in 33–40 fractions. In addition, adjuvant radiotherapy is often administered to clinically uninvolved lymph nodes of the neck, commonly to a dose of 46–50 Gy in 23–25 fractions.[4] However, optimizing the dose conformity with IMRT often requires the optimization of intensities of multiple coplanar beams, which can result in high doses of radiation to normal tissue structures and subsequent beam-path toxicities to nontarget structures.[6]

Although photon and electron beams are the primary modalities in radiation oncology, particle beams such as protons and heavy ions such as helium or neon have also been developed for cancer treatment.[5] From a physical point of view, charged particles such as protons have an evident advantage over photons. First, protons can be used to escalate the tumor dose, providing possibilities to improve local tumor control without higher doses to healthy surrounding tissue and subsequently without a higher risk for radiation-induced side effects. Second, protons can be used to deliver a lower normal tissue dose while keeping the target dose similar.[3]

A statistical approach of meta-analysis has been applied in the present article to establish conclusions for a comparative treatment plan approach of charged particle proton therapy and conventional photon therapy in treating H and N cancers (HNCs).


 > Materials and Methods Top


The aim was to conduct a literature study and apply meta-analytical approach for the evaluation of the efficacy of conventional photon radiotherapy and proton beam therapy (PBT) in the treatment of HNCs. The study followed Preferred Reporting Items for Meta-Analyses statement and was a literature-based study thus not requiring any ethical approval or informed consents from patient as no subjects were involved.

A comprehensive web-based literature search was performed using databases of PubMed, Science Direct, and Google scholar over a span of 4 months. Following this sorting of relevant articles was carried out, and results were evaluated once the selection of articles was done.

Inclusion criteria

  1. Original research articles comparing photon therapy and proton therapy for the treatment of HNCs
  2. Recent articles published 2010 onward
  3. Open access articles available for full-text download.


Exclusion criteria

  1. Studies oriented to single modality
  2. Only abstracts available, without full text for download
  3. Full-text unpublished dissertations
  4. Manuscripts in-process or unpublished articles.


Search strategy

On conducting a web-based literature search on databases with search keywords proton therapy, IMRT, intensity-modulated proton therapy (IMPT), radiotherapy, HNC, oral cancer with language restricted to English only we retrieved full-text original research articles through download in pdf format. Criteria for comparison very strictly specified for comparison of the two modalities of that comparing toxicity, locoregional failure rates, and gastrostomy tube dependency.

Only articles with this criterion were taken into consideration. Two reviewers evaluated the methodological quality of the included studies independently using the point system for critical appraisal of an article. Data were extracted from studies found to be eligible independently and stored in the form of e-information with author details, year of publication, number of patients, site of malignancy, toxicity, locoregional failure rates, and gastrostomy tube dependency. A third reviewer of higher authority was responsible for resolving any disagreement through a joint review of the article.

Statistical analysis

PAST (PAleontological STatistics) Version 3.22, Øyvind Hammer Natural History Museum University of Oslo, December 2018 was used for performing the statistics. It is statistical software for scientific data analysis, with functions for data manipulation, plotting, univariate and multivariate statistics, ecological analysis, time series and spatial analysis, morphometrics, and stratigraphy. The past went through a complete redesign in 2013. The past does work under Windows 7, Windows 10, and Mac OSX.

Mosaic plot is one of the display methods to show the outcome graphically, which shows the cell frequencies of a contingency table in which the area of boxed of the plot are proportional to the cell frequencies. Data for a mosaic plot are entered into columns. Up to four-factor variables may be used followed by an optional variable containing the counts (frequencies) for that cell. The program will tabulate data, so you do not have to use the count variable.

P value is used in the context of null hypothesis testing to quantify for significance based on mean and variance. The smaller the p-value, the higher the significance because it tells the investigator that the hypothesis under consideration may not adequately explain the observation. Here p value was set at 0.05 to prove significance, any value equal or less than this was considered to be significant [Table 1].
Table 1: Abbreviations

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 > Results Top


On carrying out a web-based search, around 300 articles were found to be relevant with study content, but every article did not fit in the study criterion. Once the criterion of comparison was set, articles were sorted accordingly and considered according to the inclusion standards. Only 5 full-text original research articles were considered to be significantly relevant and appropriate for the study postcritical appraisal [Table 2].
Table 2: Articles considered in the study

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Key points derived from review of literature

  • Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, nonadaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning[12]
  • Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage[12]
  • A reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC.[11]


The total number of patients studied was 311, out of which 194 were that for CRT and 117 for proton therapy [Figure 1] and [Figure 2].
Figure 1: Study-wise distribution of patients for conventional radiotherapy and proton beam therapy

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Figure 2: A total comparative analysis

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Evidence for toxicity variations between IMRT and IMPT by weighed analysis and static medians for research articles [Figure 3] and [Figure 4].
Figure 3: Graphical representation for weighed average

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Figure 4: Toxicity variations between intensity-modulated photon therapy and intensity-modulated proton therapy by weighed analysis and static medians

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Mosaic plots showing significant variation in toxicity according to analytical evidence based on P value estimation and percentage between CRT and PBT [Figure 5], [Figure 6], [Figure 7].
Figure 5: Mosaic plot 1

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Figure 6: Mosaic plot 2

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Figure 7: Mosaic plot 3

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Bar charts of significant toxicity variance between CRT and PBT by estimating P value and percentage of studies [Figure 8] and [Figure 9].
Figure 8: Bar chart 1

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Figure 9: Bar chart 2

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Evidence for analysis of mean dose to oral cavity IMRT versus IMPT with significance proven for lower doses to organs at risk with PBT [Figure 10].
Figure 10: Graphical representation for p-value

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Locoregional failure rates estimated comparing three high weighed articles considering 221 patients and the percentage showing high local failure rates in each study in favor of CRT [Figure 11].
Figure 11: Graphical representation for loco-regional failure

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The percentage of gastrostomy tube dependency is comparing post-treatment cases after 3–4 months of follow-up [Figure 12].
Figure 12: Graphical representation for gastrostomy tube dependency

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 > Discussion Top


The protons and Bragg peak

H and N cancers are usually treated with radiotherapy, surgery alone, or a combination of surgery and pre- or post-operative radiation therapy.[13] The inherent physical properties of proton energy deposition results in virtually no dose being delivered distal to the target make proton therapy a logical alternative to IMRT.[1] Over the past three decades, the most common method of delivering PBT has been “passive scattering” using compensators, apertures, and a range-modulation device to create a broad spread-out Bragg peak (SOBP).[14] Protons have a finite range like electrons, but at the end of their range, occurs the Bragg peak, where they deliver maximum dose. By appropriately adjusting the proton beam, Bragg peak can be positioned within tumor almost anywhere in body, sparing normal tissues both proximal and distal to tumor.[5] By varying individual proton beam energies, one can produce an SOBP that covers the tumor accurately and delivers a substantially lower dose to normal tissues beyond the tumor.[3] When the proton arrives at its target, it delivers the dose and stops, thereby eliminating an exit dose. This physical advantage serves to lower the dose to healthy organs both superficial and deep to the tumor, thus reducing the risk of injury. It also allows the administration of a higher dose to the tumor, potentially reducing the recurrence rate without increasing the complication rate and leading to better organ function and quality of life.

The cyclotron

A type of particle accelerator invented by Ernest O. Lawrence in 1929–1930 at the University of California, Berkeley, and patented in 1932. It accelerates charged particles from the center outwards along a spiral path.[15]

Pencil-beam scanning

A narrow and focused beam allows the operator to paint the marked target tumor tissue, which hypothetically bares the surrounding healthy tissue from unintended radiation exposure and its hazardous effects which could manifest as regional toxicity or treatment failure. The vast majority of published PBT studies have used passive scatter technology; the state-of-the-art technique now uses PBS. This involves precisely “painting” the target spot by spot and layer-by-layer, using a narrow beam to deposit proton dose in spots of approximately 1–2 cm.[16]

This short study meta-analysis approach measured weighed aspect to a limited number of articles to obtain results. The studies favor the results that proton therapy provides less immediate toxicity than CRT, which has high risks of immediate grade 2–3 toxicities including, dermatitis, and mucositis leading to a gastrostomy tube dependency. An analysis of the Medicare database was published more recently. An analysis by Salama et al.[16] concluded that no differences in 12-month toxicity existed. However, many of the toxicities that were evaluated were not relevant to prostate radiotherapy (e.g., upper genitourinary tract dysfunction), whereas more relevant toxicities were not considered (e.g., rectal bleeding).[17] Mean doses to the organs at risk were lower when considered for oral cavity with PBT than for X-ray therapy. The percentage of locoregional failure with conventional therapy alone was higher than that with proton therapy in present statistical comparative. As stated by Slater et al., increased locoregional control without increased toxicity is observed in patients with locally advanced oropharyngeal cancer proton therapy in HNC.[18]

Expected advantages with proton therapy

  • Improvising the amount of planned treatment dose and dose to the organs at risk
  • Laser-like precision
  • Increased locoregional control rates
  • Minimizing distant metastasis
  • Speedy treatment and recovery
  • Increment in quality life years
  • Lower risk of gastrostomy tube dependency
  • Lesser grades of toxicities.


The theoretical difference between CRT and PBT is listed [Table 3].[19]
Table 3: Difference between photon and proton-beam therapy[19]

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 > Conclusion Top


The implementation of meta-analysis approach using pooled analysis, forest plots, and Cochrane analysis may prove beneficial in providing evidence to improvise radiotherapy treatments. Unavailability of setup makes it difficult for a clinical study, instead a meta-analysis approach should be used for finding evidence and planning treatment accordingly. Furthermore, comparative preplanning could be beneficial considering multiple therapies for ruling out the best treatment outcomes that could be expected. Proton therapy being under research, still proves to be beneficial, based on our analysis in this study, yet conventional therapy is not less advantageous considering the amount of work available for any cross interpretations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Frank SJ, Cox JD, Gillin M, Mohan R, Garden AS, Rosenthal DI, et al. Multifield optimization intensity modulated proton therapy for head and neck tumors: A translation to practice. Int J Radiat Oncol Biol Phys 2014;89:846-53.  Back to cited text no. 1
    
2.
Gerber DE, Chan TA. Recent advances in radiation therapy. Am Fam Physician 2008;78:1254-62.  Back to cited text no. 2
    
3.
van de Water TA, Bijl HP, Schilstra C, Pijls-Johannesma M, Langendijk JA. The potential benefit of radiotherapy with protons in head and neck cancer with respect to normal tissue sparing: A systematic review of literature. Oncologist 2011;16:366-77.  Back to cited text no. 3
    
4.
Ask A, Björk-Eriksson T, Zackrisson B, Blomquist E, Glimelius B. The potential of proton beam radiation therapy in head and neck cancer. Acta Oncol 2005;44:876-80.  Back to cited text no. 4
    
5.
Kasat V, Vikrant V, Sahuji S, Sunil S, Joshi M, Manjiri DR. Radiotherapy: An Update. J Indian Acad Oral Med Radiol 2010;22. S26-S30. 10.5005/jp-journals-10011-1064.   Back to cited text no. 5
    
6.
Rosenthal DI, Chambers MS, Fuller CD, Rebueno NC, Garcia J, Kies MS, et al. Beam path toxicities to non-target structures during intensity-modulated radiation therapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2008;72:747-55.  Back to cited text no. 6
    
7.
Blanchard P, Garden AS, Gunn GB, Rosenthal DI, Morrison WH, Hernandez M, et al. Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer – A case matched analysis. Radiother Oncol 2016;120:48-55.  Back to cited text no. 7
    
8.
Holliday EB, Garden AS, Rosenthal DI, Fuller CD, Morrison WH, Gunn GB, et al. Proton Therapy Reduces Treatment-Related Toxicities for Patients with Nasopharyngeal Cancer: A Case-Match Control Study ofIntensity-Modulated Proton Therapy and Intensity-Modulated Photon Therapy 2015;2:19-28.  Back to cited text no. 8
    
9.
Romesser PB, Cahlon O, Scher E, Zhou Y, Berry SL, Rybkin A, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiother Oncol 2016;118:286-92.  Back to cited text no. 9
    
10.
McDonald MW, Liu Y, Moore MG, Johnstone PA. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: Cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy. Radiat Oncol 2016;11:32.  Back to cited text no. 10
    
11.
Eekers DB, Roelofs E, Jelen U, Kirk M, Granzier M, Ammazzalorso F, et al. Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial. Radiother Oncol 2016;121:387-94.  Back to cited text no. 11
    
12.
Simone CB 2nd, Ly D, Dan TD, Ondos J, Ning H, Belard A, et al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011;101:376-82.  Back to cited text no. 12
    
13.
Zackrisson B, Mercke C, Strander H, Wennerberg J, Cavallin-Ståhl E. A systematic overview of radiation therapy effects in head and neck cancer. Acta Oncol 2003;42:443-61.  Back to cited text no. 13
    
14.
Zhu XR, Poenisch F, Song X, Johnson JL, Ciangaru G, Taylor MB, et al. Patient-specific quality assurance for prostate cancer patients receiving spot scanning proton therapy using single-field uniform dose. Int J Radiat Oncol Biol Phys 2011;81:552-9.  Back to cited text no. 14
    
15.
Wikipedia contributors. Cyclotron. Wikipedia, The Free Encyclopedia. 2018. Available at: https://en.wikipedia.org/w/index.php?title=Cyclotron&oldid=927136132. [Last accessed on 2018 Jul].  Back to cited text no. 15
    
16.
Salama JK, Willett CG. Is proton beam therapy better than standard radiation therapy? A paucity of practicality puts photons ahead of protons. Clin Adv Hematol Oncol 2014;12:861, 865-6, 869.  Back to cited text no. 16
    
17.
Yu JB, Soulos PR, Herrin J, Cramer LD, Potosky AL, Roberts KB, et al. Proton versus intensity-modulated radiotherapy for prostate cancer: Patterns of care and early toxicity. J Natl Cancer Inst 2013;105:25-32.  Back to cited text no. 17
    
18.
Slater JD, Yonemoto LT, Mantik DW, Bush DA, Preston W, Grove RI, et al. Proton radiation for treatment of cancer of the oropharynx: Early experience at Loma Linda University medical center using a concomitant boost technique. Int J Radiat Oncol Biol Phys 2005;62:494-500.  Back to cited text no. 18
    
19.
Ref: Centre for Proton therapy, California. Available from: http://www.californiaprotons.com/proton-therapy. [Last accessed on 2018 Jul 26].  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

 
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