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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 975-979

Comparisons of skin toxicity in patients with extranodal nasal-type natural killer/T-cell lymphoma after treatment with intensity-modulated radiotherapy and conventional radiotherapy


Department of Radiation Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, P.R. China

Date of Web Publication11-Dec-2018

Correspondence Address:
Daoke Yang
Department of Radiation Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.192791

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 > Abstract 


Background: Intensity-modulated radiation therapy (IMRT) has been more widely used in extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) because it can maximally improve the local control rate of tumor and reduce the radiation dose received by surrounding normal tissues. However, there has been no consensus on whether IMRT can help to lower the toxic and adverse reactions caused by radiation therapy. The aim of this study is to compare skin toxicity caused by IMRT and conventional radiotherapy in Stage I–II NKTCL.
Methods: A total of 93 patients with Stage I–II NKTCL, nasal-type arising in the nasal cavity were consecutively treated using curative radiotherapy between April 2005 and August 2014. These patients received radiotherapy without chemotherapy. Definitive radiotherapy was conducted using conventional radiotherapy in 33 patients and IMRT in the other sixty patients with a regional field and a total dose of 50 Gy. Dosimetric parameters of radiation treatment plans and skin toxicity were analyzed and compared between conventional radiotherapy and IMRT.
Results: From the dosimetric analysis, IMRT demonstrated significantly improved dose coverage and homogeneity than conventional radiotherapy. Meanwhile, the Grade 1, 2, and 3 skin toxicity incidences in conventional radiotherapy group were 42.4%, 39.4%, and 18.2%, and in IMRT group were 25.0%, 31.7%, and 43.3%, respectively. Our data suggested that the severity of skin toxicity in IMRT group was statistically higher than that in conventional radiotherapy group.
Conclusions: IMRT provided improved dose coverage than conventional radiotherapy. However, IMRT failed to lower patients' risks for skin toxicity and may have the potential to increase skin toxicity.

Keywords: Conventional radiotherapy, extranodal nasal-type natural killer/T-cell lymphoma, intensity-modulated radiotherapy, skin toxicity


How to cite this article:
Gu Y, Yu H, Zuo X, Cao Q, Liang T, Ren Y, Yang H, Yang D. Comparisons of skin toxicity in patients with extranodal nasal-type natural killer/T-cell lymphoma after treatment with intensity-modulated radiotherapy and conventional radiotherapy. J Can Res Ther 2018;14, Suppl S5:975-9

How to cite this URL:
Gu Y, Yu H, Zuo X, Cao Q, Liang T, Ren Y, Yang H, Yang D. Comparisons of skin toxicity in patients with extranodal nasal-type natural killer/T-cell lymphoma after treatment with intensity-modulated radiotherapy and conventional radiotherapy. J Can Res Ther [serial online] 2018 [cited 2019 Nov 22];14:975-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/975/192791




 > Introduction Top


Extranodal nasal-type natural killer (NK)/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma, which has been formally identified and classified as a distinct clinicopathologic entity according to the WHO classification in 2001.[1],[2] Mainly depending on the primary site involved, this disease is heterogeneous in its clinical presentation, response to treatment, and prognosis. Recent studies have shown that it has at least two subtypes: NKTCL of the upper aerodigestive tract and NKTCL of the extra-upper aerodigestive tract.[3],[4] NKTCL frequently destroys the facial midline of the upper aerodigestive tract and spreads to or relapses at extranodal sites including skin, gastrointestinal tract, bone marrow, lung, extremities, orbit, adrenal gland, testis, or the central nervous system.[5],[6] Although approximately 80% of the cases diagnosed with localized disease are of Stage I–II,[7] relapse rate is high (17–77%) and the 5-year overall survival rates of this malignancy reported in recent reports are only in the order of 50%.[8] In comparison to other subtypes of non-Hodgkin lymphoma, NKTCL is relatively resistant to anthracycline-based chemotherapy. As it demonstrates a rapid and dramatic response to radiotherapy,[7],[9] now radiotherapy is the main therapeutic method for NKTCL nasal-type, but the construction of feasible and optimal patterns of radiotherapy is critical.[2]

Although the improvement of treatment devices and modification in radiation technology are inspiring, the incidence rate of radiotherapy-induced adverse reactions is still high. The most common complication in radiotherapy is skin toxicity, though the skin is not a dose-limiting tissue, skin toxicity is associated with impairment of patients' quality of life, causes pain and discomfort and limits activities. The manifestations are pruritus, erythema, pigmentation, dry desquamation, blistering, and anabrosis, as well as ulcers and necrosis in severe cases. The patients always suffer from mild to severe pain, which compromised patients' quality of life and obstruct the execution of radiation therapy. The challenge is to minimize these side effects without losing efficacy of the treatment.

In this study, we compared the two radiotherapy techniques, conventional radiotherapy and intensity-modulated radiation therapy (IMRT) for the treatment of NKTCL using statistically valid methodologies. Conventional radiotherapy and IMRT were compared in terms of differences in planning target volume (PTV) dose coverage. Moreover, the radiotherapy-related adverse events of these two techniques were analyzed, particularly regarding skin toxicity.


 > Methods Top


Study design and participants

This single-center retrospective, randomized trial was performed between April 2005 and August 2014 at Department of Radiation Oncology in our hospital. Ninety-three continuously treated patients who had pathological diagnoses of extranodal NKTCL, nasal-type arising in the nasal cavity (57 males and 36 females) were selected, aged from 21 to 70 with a median age of 44 years old. Patients with previous head and neck irradiation exposure were excluded. Thirty-three cases in conventional radiotherapy group and sixty cases in IMRT group were selected. Ann Arbor lymphoma staging classification[5] was adopted, and 61 patients were in Stage I and 32 patients were in Stage II.

The pretreatment evaluation for all patients consisted of a complete history and physical examination; complete blood count; liver and renal function tests; serum lactate dehydrogenase (LDH) measurement; biopsy of the primary lesion; direct nasopharyngeal endoscopy; computed tomography (CT) scans of the head and neck, chest, and abdomen/pelvis; and bone marrow aspiration. All patients provided written informed consent. Patients' characteristics are listed in [Table 1].
Table 1: Patient characteristics

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Evaluation methods

LDH plasma levels were measured using the LDH substrates method (Beckman Coulter Experiment System Co., Ltd., Suzhou, China). The normal range of LDH used was 0.0–247.0 U/L.

The Eastern Cooperative Oncology Group score was measured as follows:[10]

  • 0 – Asymptomatic (fully active, able to carry on all predisease activities without restriction)
  • 1 – Symptomatic but completely ambulatory (restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature. For example, light housework and office work)
  • 2 – Symptomatic, <50% in bed during the day (ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours)
  • 3 – Symptomatic, >50% in bed, but not bedbound (capable of only limited self-care, confined to bed or chair 50%, or more of waking hours)
  • 4 – Bedbound (completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)
  • 5 – Death.


Radiation therapy techniques

In the conventional radiotherapy, the patients were lying in a supine position with a U-shaped thermoplastic mask. The 0° X-ray radiation field was given and set the PTV geometric center as the field center. The prescription dose to the field center was for 40 Gy in 25 fractions at 1.6 Gy/day for 5 days/week. Concurrently, a 15-MeV electron beam was used. The 0° electron field was given and set 5 cm under the subcutaneous tissue as the beam center. The prescription to the center of maximum absorption depth (2 cm under the subcutaneous tissue) was for 10 Gy in 25 fractions at 0.4 Gy/day for 5 days/week. The dose to treatment volume and normal tissue can be calculated. The total prescription was for 50 Gy in 25 fractions at 2 Gy/day for 5 days/week.

Patients receiving IMRT were immobilized in a supine position with head, neck, and shoulder fixed with thermoplastic masks. A CT radiotherapy simulator with a layer thickness of 3 mm and slice interval of 3 mm was used for an enhanced CT scan. Scan range was from roof of the skull to inferior of the clavicular heads. CT images were transmitted to a three-dimensional treatment planning system.

The gross tumor volume (GTV) was determined according to CT or MRI analysis and endoscopic findings. The clinical target volume (CTV) consisted of the GTV and adjacent structures with potential involvement. If the neck lymph nodes were involved, the ipsilateral neck was irradiated. No prophylactic cervical irradiation was delivered. The CTV was expanded by 5 mm to obtain the PTV.

Dose-volume histogram (DVH) was used to assess the treatment plan. It was required that 100% of the PTV volume received at least 95% of the prescription dose, and more than 95% of the PTV volume received a 100% prescription dose. The dose constrictions of the organs at risks were as following:[11] parotid, 50% volume dose <30 Gy; optic nerve and chiasm, maximum dose <54 Gy; spinal cord, maximum dose ≤45 Gy; temporal lobe, maximum dose <50 Gy; lens, maximum dose <6 Gy; and brain stem, maximum dose <50 Gy. For IMRT planning, seven fields (240°, 280°, 320°, 0°, 40°, 80°, and 120°) were given. The prescription was for 50 Gy in 25 fractions at 2 Gy/day for 5 days/week.

Skin toxicity related to radiotherapy

Radiation-induced skin toxicity grading standards compiled by the criteria of the Radiation Therapy Oncology Group/European Organization for Research and Treatment Cancer[12] were adopted for the assessment of acute radiation skin reactions: Grade 0, no change in radiation field skin; Grade 1, follicular dull red erythema, alopecia, dry desquamation, or decreased sweating in radiation field skin; Grade 2, tenderness, fresh-colored erythema, patchy moist desquamation, or moderate edema of radiation field skin; Grade 3, fused moist desquamation or pitting edema except radiation field skin folds; and Grade 4, ulcers, bleeding, or necrosis occurring to radiation field skin.

Comparison criteria for the radiation treatment plans

We used Pinnacle (Philips Radiation Oncology Systems, Milpitas, CA, USA) to evaluate both radiation treatment plans. The data from the DVHs obtained from each patient were analyzed. The dose coverage was analyzed according to the minimum dose (Dmin), maximum dose (Dmax), conformity index (CI), and homogeneity index (HI).

The CI was defined as following:[6]

CI = (TVRI/TV) × (TVRI/VRI).

Where TVRI= target volume covered by the reference isodose, TV = target volume, and VRI= volume of the reference isodose. In practice, the isodose usually corresponds to the ICRU isodose 95%.[6] The value of CI is between 0 and 1, and a CI value of 1.0 indicates that the volume of the prescription isodose surface is equal to that of the PTV, which is the ideal value.

The HI was defined as following:[13]

HI = D5%/D95%.

Where Dx% represents the dose delivered to x% of the PTV. The higher the HI value, the more than the prescribed dose. Lower HI values indicate a more homogeneous target dose.

Statistical methods

SPSS Statistics 19.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Chi-square test was used for enumeration data. The Kendall tau-b rank correlation analysis was used to evaluate the association between clinical stage and the skin toxicity. P < 0.05 was considered significant.


 > Results Top


Treatment plan: Dose coverage

Parameters related to dose coverage planning for conventional radiotherapy and IMRT are presented in [Table 2]. The results indicated that IMRT showed improved PTV coverage. The Dmin and Dmean for IMRT were 19.84 Tra. 17 Gy and 52.99 Gya. 83 Gy, whereas that for conventional radiotherapy was 16.03 iot. 39 Gy and 47.83 Gyt. 15 Gy (P < 0.001). However, this advantage for IMRT was not observed for the comparison of Dmax. The IMRT plan delivered more conformal and homogeneous tumor dose distributions than conventional radiotherapy did with significant difference (P < 0.001).
Table 2: Statistics of dose-volume histograms for target volume

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Skin toxicity

All patients experienced mild to severe skin toxicity of radiotherapy. Radiation-induced skin toxicity of patients in both groups became more severe with more advanced clinical stage, and the difference displayed a statistical significance [Table 3]. The incidence rate of Grades 1, 2, and 3 skin injuries of conventional radiotherapy group was 42.4% (14/33), 39.4% (13/33), and 18.2% (6/33), and in IMRT group were 25.0% (15/60), 31.7% (19/60), and 43.3% (26/60), respectively. There were no Grades 0 and 4 cases in either group, and the incidence rate of Grade 3 radiation-induced skin toxicity of patients in conventional radiotherapy group was significantly higher than that of IMRT group [Table 4].
Table 3: Skin toxicity of patients in conventional radiotherapy group and intensity-modulated radiation therapy group with different clinical stages

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Table 4: Skin toxicity of patients in conventional radiotherapy group and intensity-modulated radiation therapy group with different grades

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 > Discussion Top


NKTCL is the most common form of mature NK/T in China, accounting for 30% of all cases.[14] It is characterized by clinical heterogeneity based on clinical prognostic factors and survival outcome.[5] It has been demonstrated that for patients with Stage I–II NKTCL, IMRT provided better dose coverage and homogeneity than conventional radiotherapy. However, there is no consensus on whether IMRT can help to lower the toxicity and reduce adverse reactions.

This study revealed that for the NKTCL patients received radiotherapy, the severity of skin toxicity in IMRT group was statistically higher than that in conventional radiotherapy group (P < 0.05). There are several reasons that could lead to the skin toxicity difference. First, a U-shaped thermoplastic head mask was used in conventional radiotherapy group, while the thermoplastic head, neck, and shoulder mask was used in patients in IMRT group. For the patients in IMRT group, although the fixation effect was improved, the surface dose of neck skin was higher than conventional radiotherapy group. Li et al.[15] used 6 MV photon and electron beams with two energies of 6 MeV and 9 MeV to test four types of thermal plastic immobilization membranes, which are the enhancement type with a design of enhanced retraction force, the extension type with a design of extended stretched length, the coated type with a coated and anti-adhesion design, and the uncoated type with an uncoated and anti-adhesion design, respectively. They found that the surface dose of the skin increased with all thermal plastic immobilization masks, and the dermal layer doses increased to 9.6% of maximum at 6 MeV electron energy. There are several reasons for thermal plastic immobilization membrane to increase the surface dose. The scattered rays generated by radioactive rays in the thermal plastic mask are the main cause for the increase in surface dose. Before X-rays enter the human body, they will react with the treatment head of linear accelerator, secondary collimator, and air to generate secondary electrons, which is called electronic pollution and can play important roles in increasing the surface dose.

Second, the isocenter and source-skin distance radiation technique are commonly used in conventional radiotherapy. Due to the dose buildup effect of high-energy X-ray, its maximal absorption dose was over 0.5 cm subcutaneously, which effectively reduced the skin superficial dose. During the target volume delineation in IMRT, except that cervical lymph node metastasis invades the skin, generally the PTV margins are below the skin surface to reduce the skin surface dose and protect the skin. However, the NKTCL is sensitive to radiotherapy, and the tumor regression is relatively marked. In addition, due to the particularity of its anatomic site, as well as the radiation therapy, NKTCL patients inevitably have the change of acute mucositis in the oral cavity, oral pharynx, and laryngeal pharynx within the radiation field, which causes a direct influence on patients' appetite and dysphagia. All these effects will result in a decrease in patients' body mass, as well as malnutrition. There has been no statistical data in the evaluation of weight loss and body mass index in relation to radiotherapy in NKTCL patients. An observational, cross-sectional study on dysphagia after head and neck radiotherapy was conducted by Szczesniak.[16] Of the 116 patients who had received radiotherapy, the response rate was up to 72%; impaired swallowing was reported by 59% of patients. Ng et al.[17] studied the nutritional status of nasopharynx cancer patients was assessed serially before and after radiotherapy. There was a significant reduction in mean BMI at the end of radiotherapy. Eighty-seven percent of patients had sustained the weight loss of >5%, and 53% had the weight loss of >10% by the end of RT and mean percentage weight loss was 10.8% at the end of RT. Therefore, the PTVs that are above the skin surface will be closer to the skin surface due to the regression of cervical enlarged lymph nodes or body weight loss in NKTCL patients during IMRT, and the skin may even be within the PTVs, which considerably increases the radiation dose of skin surface and results in the aggravation of skin injuries.

At present, IMRT has been more and more frequently used in NKTCL treatment because it can maximally improve the local control rate of tumor and reduce the radiation dose of surrounding normal tissues. Although the application of new technology can increase the conformity of target volumes and the target volume dose, the radiation volume of surrounding normal tissues is also increased so that normal tissues will receive more low-dose radiations. There is a phenomenon called low-dose hyper-radiosensitivity (HRS), which denotes an effect in which cells die from excessive sensitivity to low doses (<0.5 Gy) of ionizing radiation. HRS may be one of the reasons which cause an increase in the severity of radiation-induced skin toxicity.

To improve the radiation-induced skin toxicity, we can pay attention to the following points to relieve the skin toxicity in NKTCL patients receiving the IMRT treatment: (1) thermoplastic films can be windowed at sites where skin toxicity are apt to occur (such as the junction between middle neck and lower neck, skin with enlarged lymph nodes, as well as places with many skin folds), (2) nutritional support should be strengthened before and during radiotherapy, and enteral nutrition through nasogastric feeding tube is given to help patients to gain weight, if necessary, and (3) for patients who have the obvious regression in cervical lymph node or the weight loss, re-position, field reduction, and re-delineation of target volumes should be performed to reduce the skin toxicity.

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (Grants U1404308).

Financial support and sponsorship

This study was funded by the National Natural Science Foundation of China (Grants U1404308).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.  Back to cited text no. 10
    
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Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76 3 Suppl: S10-9.  Back to cited text no. 11
    
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Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6.  Back to cited text no. 12
    
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Mock U, Georg D, Bogner J, Auberger T, Pötter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004;58:147-54.  Back to cited text no. 13
    
14.
Liang Q, Ye ZY, Su ZL, Lin HL, Shao CK, Lin SX, et al. Clinicopathologic study of 963 cases of mature T-cell and natural killer/T-cell lymphoma with respect to 2008 WHO classification of lymphoid neoplasms. Zhonghua Bing Li Xue Za Zhi 2010;39:291-5.  Back to cited text no. 14
    
15.
Li CJ, Hu YM, Wang LZ, Quan H. Evaluation of build-up dose under thermal plastic immobilization device. Clin Eng 2010;25:98-9.  Back to cited text no. 15
    
16.
Szczesniak MM, Maclean J, Zhang T, Graham PH, Cook IJ. Persistent dysphagia after head and neck radiotherapy: A common and under-reported complication with significant effect on non-cancer-related mortality. Clin Oncol (R Coll Radiol) 2014;26:697-703.  Back to cited text no. 16
    
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Ng K, Leung SF, Johnson PJ, Woo J. Nutritional consequences of radiotherapy in nasopharynx cancer patients. Nutr Cancer 2004;49:156-61.  Back to cited text no. 17
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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