|Year : 2022 | Volume
| Issue : 3 | Page : 243-249
Skin sparing in intensity-modulated radiation therapy of nasopharyngeal carcinoma
Misba Hamid Baba1, Benoy K Singh2, Shaq ul Qamar Wani3
1 Department of Physics, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh; Department of Radiological Physics and Bio-Engineering, Srinagar, Jammu and Kashmir, India
2 Department of Physics, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh, India
3 Department of Radiation Oncology, Sher I Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
|Date of Submission||12-Apr-2022|
|Date of Decision||04-May-2022|
|Date of Acceptance||30-May-2022|
|Date of Web Publication||8-Nov-2022|
Dr. Misba Hamid Baba
Room No 255, Department of Radiological Physics and Bio-Engineering, Sher I Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Purpose: Radiation therapy of nasopharyngeal carcinomas (NPCs) involves high doses to the target structures which are superficial to the skin surfaces. As a result, the skin toxicities involved are higher and sometimes worsens to such an extent that radiotherapy needs to be interrupted unplanned. This leads to a break in radiation therapy which overall affects the local control and cure rates. The aim of this study is to decrease the skin dose by contouring skin as an organ at risk (OAR) to include in inverse planning calculation. Materials and Methods: Seventy-three cases of nasopharyngeal cancers were planned for 60 Gy to intermediate-risk planning target volume (PTVIntermediate) and 70 Gy to high risk (PTVHigh), by three different modes of Intensity-modulated radiation therapy (IMRT)- namely conventional sequential intensity-modulated radiation therapy (S-IMRT PH-I and PH-II), Skin Spared sequential intensity-modulated radiation therapy (SS-IMRT PH-I and PH-II), and Skin Spared simultaneously instantaneous boost intensity-modulated radiation therapy (SS-SIB IMRT). The plans were compared by dose volume histograms and dose statistics to the PTV as well as to the OAR's. For PTV, mean dose (Dmean), maximum dose (Dmax), and minimum dose (Dmin) were compared to check the homogeneity index (HI) while sparing the skin. For other OAR's Dmean, Dmax and dose to to 1 cubic cm was used for comparison. The skin doses to various volumes from volume to receive 5 Gy (V5) to volume to receive 70 Gy (V70) were evaluated and compared between the three techniques. Statistical analysis was done using one away ANOVA on the data editor SPSS Version 26.0 (SPSS Inc., Chicago, Illinois, USA) to evaluate the results. Continuous variables were expressed as mean ± standard deviation, and categorical variables were summarized as frequencies and percentages. Survival analysis was done by Kaplan–Meier Estimator. Results: When the skin was considered as an OAR, the skin volume to receive 5, 10, 15, 20, 30, 40, 50, 60, 70 Gy was reduced by 6.5%, 6.5%, 6%, 11.5%, 7%, 6%, 6%, 5%, 2%, respectively, by SS-IMRT PH-I and II and 2%, 4.05%, 4%, 7%, 5%, 3%, 6%, 5%, 1%, respectively, by SS-SIB IMRT when both the SS techniques were compared with S-IMRT PH-I and II. Volume of skin to receive 20 Gy showed maximum reduction in SS-IMRT PH-I and II. A one-way ANOVA was carried out to find the differences in the skin doses between the three techniques. The skin dose in the two SS techniques, i.e., SS-IMRT PH-I and PH-II and SS-SIB IMRT was found significantly lower than that of IMRT plans without skin as an OAR, i.e., S-IMRT PH-I and PH-II (P = 0.000). The PTV doses were well within the 95%–107% of the prescribed dose (HI) and there were no significant differences in the means of the prescribed dose between the simple and skin spared IMRT techniques. The other OARs doses were also evaluated and there were no significant differences between the means of the doses among the techniques. Conclusions: SS IMRT for NPC has demonstrated reduction in skin dose while using skin as an OAR in the optimization. Moreover, decreased skin dose can decrease the skin related toxicities provided there is no compromise on Target dose coverage and OAR dose. We recommend that skin should be contoured as an OAR for NPC, provided PTV is minimally 3–5 mm beneath skin surface, in order to have a better disease control with lesser toxicities and less unplanned treatment interruptions.
Keywords: Nasopharyngeal carcinoma, organ at risk, simultaneously instantaneous boost, skin sparing
|How to cite this article:|
Baba MH, Singh BK, Wani SQ. Skin sparing in intensity-modulated radiation therapy of nasopharyngeal carcinoma. J Med Phys 2022;47:243-9
|How to cite this URL:|
Baba MH, Singh BK, Wani SQ. Skin sparing in intensity-modulated radiation therapy of nasopharyngeal carcinoma. J Med Phys [serial online] 2022 [cited 2022 Dec 7];47:243-9. Available from: https://www.jmp.org.in/text.asp?2022/47/3/243/360592
| Introduction|| |
Nasopharyngeal carcinoma (NPC) is an uncommon cancers that is endemic to east and southeast Asia (70% of the cases). It is the 23rd most common type of cancer worldwide. Although rare the men are at higher risk to develop nasopharyngeal cancers than females and are approximately twice as common in men as in women. It is the 18th most commonly occurring cancer in men and the 22nd most commonly occurring cancer in women. There were an estimated 133,354 cases of NPCs with a mortality of about 80,008 in 2020 and the projected 5-year prevalence is 382,507 cases. Overall incidence rates are three times higher in middle- to low-income countries than in high-income countries. Among Asian countries, India has the fourth most common incidence of carcinoma nasopharynx. In addition to geographic diversity, it seems that some ethnic groups are prone to nasopharynx cancer. These groups include the Bidayuh in Borneo, the Nagas in northern India, and the Inuits in the North pole. The highest rates are found in South-East Asia, in particular among Cantonese people living in the central region of Guangdong Province in southern China. The risk factors include dietary products such as consuming Cantonese-style salted fish,, red meat, processed meat, and preserved nonstarchy vegetables. In addition to the findings on diet, nutrition, physical activity, other established causes of nasopharyngeal cancers include, smoking, occupational exposure, infectious agents like Epstein–Barr virus, family history., Nasopharyngeal cancer as per our hospital based cancer registration is not common in our region. It accounts only for 2% of the total cases registered in our hospital. The incidence varies from 1% to 5% per year. Treatment options and recommendations depend on several factors, including the type and stage of cancer, possible side effects, and the patient's preferences and overall health. The main treatment for NPC recommended by the American Society of Clinical Oncology (ASCO) is the radiation therapy. It is usually given in combination with chemotherapy as concurrent chemoradiation.,, Surgery is sometimes needed mainly to remove lymph nodes after chemoradiation or in case of recurring disease. Radiation therapy to nasopharynx is usually best delivered by intensity-modulated radiation therapy (IMRT) that allows more effective doses of radiation to be delivered, at a better sparing of organs at risk (OAR's) surrounding the nasopharynx. ASCO, the European society for medical oncology recommends concurrent chemoradiation as a treatment of choice as a treatment of choice for all the stages from stage II to stage IV disease., Brachytherapy is also used to treat NPCs but as the procedures being invasive and cumbersome in nature only few radiotherapy centers offer this treatment. As the external beam radiation therapy curative doses for NPCs are as high as 70 Gy to the target structures, i.e., nasopharynx and nodes which are superficial and near to the skin surfaces, the skin toxicities becomes the major cause of unplanned treatment interruption during the course of radiotherapy, which can affect the local control as well as the overall survival of the patient. In this study, we aimed to decrease the skin dose to some extent by contouring skin as an organ at risk (OAR), which usually is not contoured as an OAR for head and neck irradiations. Few authors have recently published on the feasibility of skin sparing (SS) in NPC and thus an attempt was made by us to achieve few benefits from the same using the available resources for a resource limited radiotherapy center like ours.
| Materials and Methods|| |
Patient selection and radiotherapy planning
Seventy-three cases of NPC patients registered from 2016 to 2021 receiving adjuvant radiation therapy of 70 Gy were selected for the study. Computed tomography scanning-based simulation of all the patients was done using a head and neck thermoplastic cast from Klarity® on the wide bore computed tomography (CT) scanner (M/s Semiens Somatom Sensation) with contrast dye. The slice thickness of the scan was 3 mm for IMRT. All the scans were taken in supine position. The CT datasets in digital imaging and communications in medicine format were transferred to the EclipseTM treatment planning system (Ver. 13.6) in which the Somavision workstation was used to delineate the targets and OAR's. The targets and OAR's volumes were defined as per international commission on radiation units and Measuremen Reports 50 and 62 recommendations. The doses were optimized according to the dose recommendations from radiation therapy oncology group (RTOG) and qualitative analysis of normal tissue effects in the clinic. Usually, skin is not contoured as OAR for NPCs, but for these 73 patients 3 mm skin inside the body was contoured as an OAR. Study patients were divided in three planning groups namely Group I that received 70 Gy by conventional sequential IMRT (S-IMRT PHI and PHII), Group II-Skin Spared sequential IMRT (SS-IMRT PHI and PHII), and Group III-Skin Spared simultaneously instantaneous boost IMRT (SS-SIB IMRT).
All the plans were planned using EclipseTM Treatment Planning System Version 13.6 by Varian Medical System, Inc., Palo Alto, CA USA. Volume dose was calculated using Anisotropic Analytical Algorithm (Version 13.6.23) with a calculation grid size of 0.25 cm and fluence was optimized using Dose Volume Optimizer (Version 13.6.23). [Figure 1] shows a representative plan of an NPC planned using (IMRT).
|Figure 1: A representative case for radiotherapy of nasopharynx planned using Intensity modulated radiotherapy|
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The plans were compared by dose-volume histograms (DVHs) and dose statistics to the planning target volume (PTV) volumes as well as to the OAR's. For PTV, Dmean, Dmax, Dmin, were compared. For OAR's Dmean, Dmax/Dmax and dose to one centimeter cube were used for comparison. The skin doses to various volumes from volume to receive 5 Gy (V5) to skin volume receiving 70 Gy (V70) were evaluated and compared.
The evaluated dose was analyzed using data editor of IBM® SPSS® V-26 (SPSS Inc., Chicago, Illinois, USA). A one-way-ANOVA analysis was used to access the difference in the skin doses between the three techniques. The comparative datasets were evaluated on a 5% level of significance i.e., P < 0.05% was considered statistically significant. The other OAR's doses were also analyzed by one-way ANOVA. The PTV dose coverage and homogeneity was also calculated and analyzed by one-way ANOVA.
| Results|| |
When the skin was considered as an OAR the skin volume to receive 5, 10, 15, 20, 30, 40, 50, 60, 70 Gy was reduced by 6.5%, 5%, 6%, 11.5%, 7%, 6%, 6%, 5%, 2%, respectively, by SS-IMRT PHI and II and 2%, 4.05%, 6%, 7%, 5%, 3%, 3%, 5%, 1%, respectively, by SS-SIB IMRT when compared with S-IMRT PHI and II. [Table 1] shows percent volume of skin (Mean ± standard deviation [SD]) to receive different doses of radiation by the three IMRT techniques. [Table 2] shows a one-way ANOVA result for Skin volume to receive 20 Gy. [Table 3] describes test of significance between three techniques for volume of skin to receive 20 Gy. [Table 4] shows overall ANOVA results for skin volume to receive 20 Gy. [Figure 2] shows DVH comparisons as well as the IMRT plans in multiplanner view (a) Conventional versus SS IMRT Plan, (b) Skin Spared sequential IMRT versus skin spared SIB IMRT (SS-SIB) plan. [Figure 3] shows graphically the difference in the mean volume of skin to receive 20 Gy by three techniques. [Figure 4] depicts the volume of skin to receive 20 Gy dose by three techniques along with the Q1, Median and Q3 values of all 73 patients.
|Table 1: Volume of skin to receive different doses by conventional sequential (sequential intensity modulated radiation therapy PHI and II), skin spared simultaneously instantaneous boost intensity modulated radiation therapy and skin spared sequential intensity modulated radiation therapy PHI and II) (P<0.05)|
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|Table 3: Test of significance between three techniques for volume of skin to receive 20 Gy|
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|Figure 2: DVH and plan comparisons in multiplanner view (a) Conventional versus skin sparing IMRT plan (b) Skin spared IMRT versus skin spared SIB IMRT (SS-SIB) Plan, IMRT: Intensity modulated radiation therapy, SS-SIB: Skin Spared simultaneously instantaneous boost, DVH: Dose volume histogram|
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|Figure 3: Graph showing the Mean Volume of skin to receive 20 Gy by three techniques|
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|Figure 4: Box plot showing volume of skin to receive 20 Gy dose by three techniques|
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Other organs at risk dose
Rest of the OAR's dose was also analyzed by one-way ANOVA. There was no significant difference (P > 0.05) between the doses to OAR's among the three techniques. [Table 1] shows the Mean ± SD, 95% confidence interval and significance values. [Table 5] shows the dose received by different OARs by three techniques and the differences in the mean as P value.
|Table 5: Organs at risk dose in three techniques of intensity modulated radiotherapy were almost same (P>0.05)|
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Planning target volume dose
The target dose was evaluated using Homogenity Index, described by RTOG formula given below, D2%, D98%, and D50%. There were no significant differences in the dose homogeneity between the three techniques. [Table 6] shows the dose homogeneity indexes (HI) to PTV in three techniques. Target dose was also evaluated for conformity using the RTOG Formula described below, and there were no significant differences in dose conformity. [Table 7] shows the dose conformity indexes to PTV in three techniques.
|Table 6: Dose homogeneity index±standard deviation to planning target volume in three techniques of intensity modulated radiotherapy (P>0.05)|
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|Table 7: Dose confidence interval±standard deviation to planning target volume in three techniques of intensity modulated radiotherapy (P>0.05)|
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Homogeneity index=, Where D2%, D98%, D50% is the dose to 2, 98 & 50% volume of the target.
Conformity index RTOG = VRI/TV, Where VRI = Reference isodose volume (D95) and TV = Target volume.
| Discussion|| |
NPC accounts for the 2% of all the head and neck cancers., Treatment modality is mostly radiotherapy with a good survival rate., During 2016–2021, a total of 114 NPC patients were registered at our institution, 73 out of 114 patients were enrolled in this study and were treated by intensity-modulated radiation therapy. The overall survival was 74% with a mean survival of 4.731 years [[Figure 5] KP-survival]. All the patients received 60 Gy to PTV Intermediate and 70 Gy to PTV High at 2 Gy per fraction as recommended by various protocols. Further, the feasibility of SS was assessed by re-planning all the 73 cases with skin as an OAR by skin spared IMRT and SIB IMRT and the differences in the various volumes to receive various doses from DVHs were quite significant. Skin volume to receive 5, 10, 15, 20, 30, 40, 50, 60, 70 Gy all reduced significantly when skin was considered as an OAR in the two SS IMRT techniques, but the volume to receive 20 Gy was maximally reduced by 11.5% in SS-IMRT PHI and II and 7% by SS-SIB IMRT (2, 3 and 4). Our results are consistent with a study done by Liao et al. to evaluate the feasibility of a skin dose reduction in the treatment of NPC by comparing the skin dose reduction obtained by three different treatment modalities, i.e., IMRT, Volume modulated arc radiation therapy (VMAT) and helical tomotherapy with skin as an OAR without compromising the PTV dose. They concluded when skin was considered as an OAR the skin volume to receive more than 30 Gy was reduced by 3.7% by IMRT, 4.1% by VMAT, and 4.3% helical tomotherapy. In our case as we are not having higher state of art of radiotherapy delivery than IMRT, and our center being a resource limited center, we compared the simple IMRT plans with skin spared IMRT plans to reduce the dose to skin by some amount and found a significant decrease in the same. Another study on SS IMRT by Saibishkumar et al. performed for early-stage breast cancer suggests that doses delivered to skin were significantly lower in plans with skin as an OAR and there was an overall reduction in skin dose from 57.8% to 12.2%. The reduction in dose was evaluated dosimetrically by thermoluminescence detectors measurements on anthropomorphic phantom. We also confirmed the dose reduction in vitro on anthropomorphic phantom by Gafchromic film dosimetry and found the dose differences of 10.9% ± 0.12% between simple IMRT and Skin Spared IMRT Plans [Figure 6]. The PTV dose evaluated for the HI to justify the SS without compromising the target dose also remained unvaried (P > 0.05). OARs other than skin also remained unvaried between the skin spared and nonskin spared IMRT techniques (P > 0.05) which is similar to the study done by Liao et al.
|Figure 6: In vitro verification of dose difference to the skin by skin spared IMRT using Gafchromic film dosimetry, IMRT: Intensity modulated radiation therapy|
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| Conclusions|| |
SS IMRT for head and neck cancers can be useful to bring down the skin dose as well as the toxicities to some extent. This study also tried to apply the SS in IMRT and we found that a good amount of skin dose decreased in SS IMRT. Therefore, we conclude that the skin should be contoured as an OAR for the IMRT planning of NPC s where the target is minimally 3–5 mm below the skin. The same strategy could be useful in other head and neck irradiations as far as the disease is not on the skin. Furthermore, this technique can yield lesser toxicities and less unplanned treatment interruptions which otherwise affects the overall treatment time and disease control
The drawbacks of our study were that in this study we compared only treatment planning system calculated dose for SS by three techniques. In future SS IMRT irradiations for NPC could be evaluated for locoregional disease control, skin toxicities as well as the overall survival. Furthermore, TPS calculated skin doses can be measured in vivo to find the difference in the calculated and measured doses.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Mahdavifar N, Ghoncheh M, Mohammadian-Hafshejani A, Khosravi B, Salehiniya H. Epidemiology and inequality in the incidence and mortality of nasopharynx cancer in Asia. Osong Public Health Res Perspect 2016;7:360-72.
Wee JT, Ha TC, Loong SL, Qian CN. Is nasopharyngeal cancer really a “Cantonese cancer”? Chin J Cancer 2010;29:517-26.
Yu MC, Mo CC, Chong WX, Yeh FS, Henderson BE. Preserved foods and nasopharyngeal carcinoma: A case-control study in Guangxi, China. Cancer Res 1988;48:1954-9.
Yu MC, Ho JH, Lai SH, Henderson BE. Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: Report of a case-control study in Hong Kong. Cancer Res 1986;46:956-61.
Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 2002;12:421-9.
Fles R, Wildeman MA, Sulistiono B, Haryana SM, Tan IB. Knowledge of general practitioners about nasopharyngeal cancer at the Puskesmas in Yogyakarta, Indonesia. BMC Med Educ 2010;10:81.
Aiyar A, Tyree C, Sugden B. The plasmid replicon of EBV consists of multiple cis-acting elements that facilitate DNA synthesis by the cell and a viral maintenance element. EMBO J 1998;17:6394-403.
Khan NA, Ahmad SN, Dar NA, Masoodi SR, Lone MM. Changing pattern of common cancers in the last five years in Kashmir, India: A retrospective observational study. Indian J Med Paediatr Oncol 2021;42:439-43.
Chen QY, Wen YF, Guo L, Liu H, Huang PY, Mo HY, et al.
Concurrent chemoradiotherapy vs. radiotherapy alone in stage II nasopharyngeal carcinoma: Phase III randomized trial. J Natl Cancer Inst 2011;103:1761-70.
Xu C, Zhang LH, Chen YP, Liu X, Zhou GQ, Lin AH, et al.
Chemoradiotherapy versus radiotherapy alone in stage II nasopharyngeal carcinoma: A systemic review and meta-analysis of 2138 patients. J Cancer 2017;8:287-97.
Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, et al.
Chemotherapy and radiotherapy in nasopharyngeal carcinoma: An update of the MAC-NPC meta-analysis. Lancet Oncol 2015;16:645-55.
Chen YP, Ismaila N, Chua ML, Colevas AD, Haddad R, Huang SH, et al
. Chemotherapy in Combination With Radiotherapy for Definitive-Intent Treatment of Stage II-IVA Nasopharyngeal Carcinoma: CSCO and ASCO Guideline; 2021. Available from: http://hub.hku.hk/handle/10722/295516
. [Last accessed on 2022 Apr 11].
Bossi P, Chan AT, Licitra L, Trama A, Orlandi E, Hui EP, et al.
Nasopharyngeal carcinoma: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up†
. Ann Oncol 2021;32:452-65.
Syed AM, Puthawala AA, Damore SJ, Cherlow JM, Austin PA, Sposto R, et al.
Brachytherapy for primary and recurrent nasopharyngeal carcinoma: 20 years' experience at Long Beach Memorial. Int J Radiat Oncol Biol Phys 2000;47:1311-21.
Lee AW, Ng WT, Pan JJ, Chiang CL, Poh SS, Choi HC, et al.
International guideline on dose prioritization and acceptance criteria in radiation therapy planning for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2019;105:567-80.
Chavaudra J, Bridier A. Definition of volumes in external radiotherapy: ICRU reports 50 and 62. Cancer Radiother 2001;5:472-8.
Wu LR, Liu YT, Jiang N, Fan YX, Wen J, Huang SF, et al.
Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center. Oral Oncol 2017;69:26-32.
Lee CC, Huang TT, Lee MS, Su YC, Chou P, Hsiao SH, et al.
Survival rate in nasopharyngeal carcinoma improved by high caseload volume: A nationwide population-based study in Taiwan. Radiat Oncol 2011;6:92.
Liao X, Li J, Wang P, Yao X, Zhang Y, Tan T, et al.
Feasibility of a skin dose reduction for nasopharyngeal carcinoma treated with high-intensity-modulated delivery techniques. Technol Cancer Res Treat 2018;17:1533033818803582.
Saibishkumar EP, MacKenzie MA, Severin D, Mihai A, Hanson J, Daly H, et al.
Skin-sparing radiation using intensity-modulated radiotherapy after conservative surgery in early-stage breast cancer: A planning study. Int J Radiat Oncol Biol Phys 2008;70:485-91.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]