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C–Reactive Protein Levels and Radiation–Induced Mucositis in Patients With Head–and–Neck Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 2, pp. 393–398, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.11.012
CLINICAL INVESTIGATION
Head and Neck
C–REACTIVE PROTEIN LEVELS AND RADIATION–INDUCED MUCOSITIS IN PATIENTS WITH HEAD–AND–NECK CANCER YONGKAN KI, M.D.,* WONTAEK KIM, M.D.,*y JIHO NAM, M.D.,* DONGHYUN KIM, M.D.,* DAHL PARK, PH.D.,* AND DONGWON KIM, M.D.*y * Department of Radiation Oncology, Pusan National University School of Medicine, and y Medical Research Institute, Pusan National University, Busan, Korea Purpose: To evaluate the relationship between C–reactive protein (CRP) levels or the erythrocyte sedimentation rate (ESR) and the grade of acute radiation–induced mucositis in patients with head–and–neck cancer. Methods and Materials: This study was performed in 40 patients who received intensity–modulated radiation therapy as a radical treatment of primary laryngo–pharyngeal cancer. Serum CRP level and ESR were initially checked on the day of radiotherapy simulation and were measured every week during the irradiation schedule and two times biweekly after radiotherapy. Mucosal reactions were evaluated by radiation oncologists on days of blood sampling. Results: The distribution of the most severe mucositis was Grade I mucositis in 10% of the patients, Grade II in 60% of the patients and Grade III in 30% of the patients. Statistical analysis indicated a significant rise in the CRP level (p < 0.001) according to radiation fraction number and grade of mucositis. A change of the mean CRP level was correlated with progression of mean grade of mucositis according to fraction number. The ESR did not show any statistically significant relationship with radiotherapy fraction number and grade of acute mucositis. Conclusions: There was a significant correlation between the presence of acute mucositis and CRP level in this study. The CRP level could be conveniently determined along with evaluation of mucosal reactions during or after radiotherapy to provide further information on radiation–induced mucositis. Ó 2009 Elsevier Inc. C–reactive protein, Erythrocyte sedimentation rate, Intensity–modulated radiation therapy, Acute mucositis, Head–and–neck cancer.
INTRODUCTION
induced mucositis. These factors, however, provide little information to predict the course (or the degree) of acute mucositis. Acute phase reactants (APRs) are widely used clinical indicators of the inflammatory and immunologic reactions induced by injury or infection. The level of C–reactive protein (CRP), a well–studied APR, and the erythrocyte sedimentation rate (ESR) can be measured easily in the outpatient clinic as direct and quantitative markers for inflammatory activity (3). Cengiz et al. (4) showed significant rises in the ESR and CRP levels at the end of radiotherapy to the pelvic–paraaortic field. These investigators also attempted to determine whether a rise in APR was correlated with acute and late radiation morbidity (radiation enteritis). However, there was no correlation between the clinical severity of acute and chronic radiation enteritis and APR rise. Nevertheless, it would be useful for radiation oncologists to assess radiation– induced mucositis with changes in APR. We evaluated the
One of the most common complications of radiotherapy for patients with head–and–neck cancer is acute mucositis of the upper digestive tract. Severe mucositis usually causes patients swallowing difficulty and local pain, which affects compliance with radiotherapy. A previous report noted undesired interruption of radiation therapy because of moderate to severe mucositis (1). Oncologists thus need to consider the appearance and change in grade of radiation–induced mucositis. There are many treatment–related findings, widely known as risk factors for acute oral mucositis, which include age, gender, body mass index, alcohol use, tobacco use, oral hygiene, stage of disease, white blood cell count, salivary rate, and normal flora of the mouth (2). Particularly as for radiotherapy–related factors, the dose per fraction, total dose, overall treatment duration, and fractionation schedule are able to influence the occurrence and severity of radiation–
Acknowledgment—This study was supported by Medical Research Institute Grant (2006–49), Pusan National University. Received Aug 29, 2008, and in revised form Oct 27, 2008. Accepted for publication Nov 5, 2008.
Reprint requests to: Wontaek Kim, M.D. Department of Radiation Oncology, Pusan National University School of Medicine, 1–10, Ami–dong, Seo–gu, Busan, Korea. Tel: 82–51–240–7383; Fax: 82–51–248–5747; E-mail: [email protected] Conflict of interest: none. 393
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394
relationship between change in serum CRP levels and ESR and the course or degree (i.e., severity) of acute radiation– induced mucositis in patients who underwent radiation therapy for laryngo–pharyngeal cancer.
Volume 75, Number 2, 2009
method, using Modular E170 (Roche Diagnostics, Mannheim, Germany). A capillary microphotometer method was used for determination of the ESR by TEST1 (ALIFAX, Petrarca, Italy).
Analysis of acute mucositis METHODS AND MATERIALS Patients This study was designed to enroll primary laryngo–pharyngeal cancer patients who received whole–neck radiotherapy as a radical treatment between October 2005 and December 2006. The primary sites of cancer were the oropharynx, hypopharyx, supraglottis, and glottis. Clinical stages of all cases were classified according to the American Joint Committee on Cancer staging system (sixth edition) using a physical examination and imaging study. Some patients on a concurrent chemoradiotherapy (CCRT) protocol were excluded to rule out the impact of chemotherapy on acute phase reactions and symptomatic mucositis. Informed consent was obtained from all patients. This trial protocol was approved by the Institutional Review Board of our hospital.
Mucosal reactions on the irradiated field, especially the posterior aspect of the tongue and most parts of the oropharynx, were examined and described on days of blood sampling during and after radiotherapy. Acute mucositis was evaluated grossly and endoscopically by 1 radiation oncologist according to the use of the National Cancer Institute Common Toxicity Criteria (NCI CTC, version 2.0) and was confirmed by a second radiation oncologist. Each evaluation was independent. In the case that the 2 observers evaluated the grade of mucositis differently in the same patient, the higher grade was chosen. The NCI CTC for acute mucositis from radiation are the following: Grade 0, no mucositis; Grade 1, erythema of the mucosa; Grade 2, a patchy reaction #1.5 cm in diameter and noncontiguous; Grade 3, a confluent pseudomembranous reaction with contiguous patches generally greater than 1.5 cm in diameter; Grade 4, necrosis or deep ulceration including bleeding not induced by minor trauma or abrasion (5).
Radiotherapy Radiotherapy was performed with a seven–field intensity–modulated radiation therapy (IMRT) technique. Virtual simulation using computed tomography (CT) simulation and inverse radiotherapy planning were conducted to obtain conformal dose distribution over the primary tumor sites and cervical lymphatic systems. Six– megavoltage photon beams generated from a linear accelerator (Clinac 21–EX, Varian Medical Systems, Palo Alto, CA) and a dynamic multi–leaf collimator were using to deliver the intensity–modulated beam to complicated targets. The treatment targets were divided into three parts including Clinical Target Volume 1 (CTV1), Clinical Target Volume 2 (CTV2), and Clinical Target Volume 3 (CTV3). The primary tumor and enlarged lymph nodes, including a safety margin, denoted as CTV1. The boundary of CTV2 was the anatomical compartment and adjacent lymphatic systems embracing CTV1. The CTV3 was determined as the area that received elective radiation. The simultaneous integrated boost (SIB) technique was applied to administer different doses to each target. The total radiation dose was 70.0 to 74.2 Gy in 35 fractions to CTV1, 63.0 to 66.5 Gy to CTV2, and 56.0 to 59.5 Gy to CTV3. More than 54 Gy was planned to be delivered to clinically significant cervical lymph node levels such as Level II, III, IV, and V. The Level Ib lymphatic area was occasionally irradiated with more than 50 Gy. Most of the oral mucosa and some of the oropharyngeal mucosa in all patients were delineated, and the 10% and 50% volumes of these areas were constrained to receive a dose of less than 60 Gy and 40 Gy, respectively. Other important organs at risk such as the spinal cord, brainstem, and superficial lobes of the parotid glands were also contoured and were planned to receive less than 44 Gy, 50 Gy, and 20 Gy, respectively.
Analysis of CRP level and ESR Serum CRP levels and ESR were initially checked on the day of CT simulation. Subsequently the serum CRP level and ESR were measured every week during the irradiation schedule and two times biweekly after the end of radiotherapy. Blood sampling was performed approximately 1 h after irradiation. The start of radiotherapy was delayed 2 to 3 weeks for 8 patients who had received several cycles of induction chemotherapy so as to reduce the indefinite side effects of the systemic cytotoxic agents. The level of CRP was measured with an electrochemiluminescence immunoassay
Statistical analysis The Kruskall–Wallis test was used for the analysis of the relationship between changes in CRP levels and ESR and the grade of radiation–induced mucositis. Statistical analysis for the correlation between the radiotherapy fraction numbers and the serum concentration of CRP or the ESR or the grade of mucositis was determined by use of the paired t test. Mean values of the APR level and grade of mucositis according to the fraction numbers were used, instead of each maximum value, to evaluate the positive correlation. Statistical analyses were performed with SPSS software (SPSS Inc., Chicago, IL). A p value of less than 0.05 was regarded as statistically significant.
RESULTS A total of 52 patients were initially included in this study. However, 4 patients were unable to complete their whole course of radiotherapy in 80 days because of personal problems, and 8 patients refused sequential blood samplings in the course of radiotherapy. Ultimately, 40 patients underwent the radiation therapy schedules. The patients underwent periodic testing of CRP levels and ESR, and mucosal reactions were evaluated. Characteristics of the patients are summarized in Table 1. All of the patients were diagnosed with one or Table 1. Characteristics of the study patients Characteristic
Patients (n) (N = 40)
Median age, y (range) Male:Female Site Oropharynx Hypopharynx Supraglottis Glottis AJCC Stage III IVA IVB
61 (47–69) 32:8
%
14 8 10 8
35 20 25 20
6 32 2
15 80 5
Abbreviation: AJCC = American Joint Committee on Cancer.
CRP and radiation–induced mucositis d Y. KI et al.
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Table 2. Mean C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR) according to radiotherapy schedules (fraction numbers) CRP level (mg/dl)
ESR (mm)
Radiotherapy schedule
Mean
SD
Mean
SD
Pre-RT Fraction 5 Fraction 10 Fraction 15 Fraction 20 Fraction 25 Fraction 30 Fraction 35 Post-RT Week 2 Post-RT Week 4
0.26 0.27 0.84 0.87 1.80 1.93 2.08 2.12 1.07 0.74
0.19 0.37 1.51 1.10 2.77 2.09 2.45 2.95 0.23 0.12
44 43 32 45 43 48 49 70 48 50
28 28 16 18 11 17 19 42 15 2
Abbreviations: Pre-RT = before radiotherapy; Post-RT = after radiotherapy; SD = standard deviation.
more cervical lymph nodes; there were no metastases to the submental lymph nodes. The mean duration of radiotherapy was 50 days (range, 45–62 days). Acute radiation–induced mucositis developed in all patients, and the distribution of the most severe mucosal reactions during the radiotherapy schedule were Grade I mucositis in 10% of the patients, Grade II mucositis in 60%, and Grade III mucositis in 30%; there was no Grade IV mucositis. The mean grade of mucositis as a function of radiation fraction number increased significantly during the radiotherapy schedule (p < 0.001; Fig. 3). The CRP levels showed a significant increase by the 15th radiotherapy fraction. Variations in the CRP level and ESR during irradiation are shown in Table 2. Mean CRP levels increased significantly during the course of fractionated radiotherapy and decreased after radiotherapy (p < 0.001); mean CRP level and ESR in accordance with the grade of mucositis are shown in Table 3. Statistical analysis demonstrated a significant rise in the mean value of the CRP level (p < 0.001) according to the fraction number and the grade of mucositis (Figs. 1 and 2). Figure 3 shows that the change in mean level of CRP was correlated with progression of the mean grade of mucositis according to the fraction number. As the mean grade of mucositis increased or decreased, the mean CRP concentration changed nearly simultaneously (correlation coefficient = 0.544, p <0.001).
Fig. 1. Changes in C–reactive protein (CRP) levels (95% confidence interval [95% CI]) according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
Hemoglobin levels were also checked, as ESR could vary with the concentration of hemoglobin; however, there was no significant change in the hemoglobin level during irradiation. The ESR did not show any statistically significant relationship with the fraction number of radiotherapy and grade of acute mucositis (p = 0.58) (Figs. 4 and 5). Mean ESR varied little with fraction number (p = 0.67). Induction chemotherapy had little effect on mean CRP. The coefficient of correlation between the group treated with induction chemotherapy
Table 3. Mean C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR) according to grade of acute radiation-induced mucositis CRP level (mg/dl)
ESR (mm)
Grade
Mean
SD
Mean
SD
0 1 2 3
0.27 0.64 1.70 3.07
0.37 0.72 2.30 3.21
43 40 50 40
26 25 24 9
Fig. 2. Changes in C–reactive protein (CRP) levels (95% confidence interval [95% CI]) according to grade of acute mucositis.
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Fig. 3. Mean C–reactive protein (CRP) levels and mean grade of acute mucositis determined according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
and the group without induction therapy was 0.828 (p = 0.006). DISCUSSION Vera–Llonch et al. (1) reported that the radiation–induced mucositis developed in 80% of head–and–neck cancer patients and that a severe mucosal reaction occurred in 29% of patients. There have been several trials to determine a correlation between radiation–induced inflammation and levels of APR. Some studies have demonstrated that radiation might be a cause of a significant change in APRs. One study
Fig. 4. Changes in erythrocyte sedimentation rate (ESR) (95% confidence interval [95% CI]) according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
Volume 75, Number 2, 2009
Fig. 5. Changes in erythrocyte sedimentation rate (ESR) (95% confidence interval [95% CI]) according to grade of acute mucositis.
showed that radiation decreased the serum transferrin level and increased the level of serum CRP, ferritin, and ceruloplasmin in cancer of the digestive tract, including head– and–neck cancer (6). Another study determined that the level of transferrin decreased, whereas the level of tumor necrosis factor–a and ceruloplasmin increased during radiotherapy for gynecologic cancer (7, 8). Tang et al. (9) observed that pelvic radiotherapy did not change the level of CRP, whereas Cengiz et al. (4) reported that pelvic irradiation in patients with gynecologic cancer was associated with an increase in CRP level and ESR. Based on these findings, it is presumed that radiation exposure has caused acute radiation–induced inflammatory reactions, leading to an increase in APR levels. Even though no definite evidence indicating a significant correlation between acute enteritis and APR levels in the study by Cengiz et al. was reported, we assumed that acute radiation–induced mucositis in the head–and–neck area may have a significant correlation with APR level. Bowel toxicities were recorded and were scored according to patient subjective symptoms and clinical signs, however, oral or oropharyngeal mucositis could be diagnosed and be evaluated by direct examination of the patients. In addition, acute mucositis at the head and neck area occurred frequently in most patients who had undergone irradiation, and the symptoms were relatively severe. More concrete supplementary data or information on radiation–induced inflammation may provide details on the relationship with APRs. We wished to evaluate the severity of radiation–induced mucositis and the change in the CRP level and ESR in the head–and–neck cancer patients, and also aimed to determine a possible correlation between serum levels of APRs and the course of mucositis. No significant clinical relation with the radiation fraction number and the severity of mucositis was correlated with a change in the
CRP and radiation–induced mucositis d Y. KI et al.
ESR in this study. The serum level of CRP showed an increasing trend with fraction number, which indicated a statistically significant correlation between the cumulative radiation dose and grade of acute radiation–induced mucositis. Our results also showed that the mean value of CRP levels increased similarly with the mean grade of mucositis during the course of fractionated radiotherapy. Simple measurement of the serum concentration of APR is possibly less sensitive and less specific for determining the inflammatory mechanism of acute mucositis and its distinct severity. Nevertheless, the CRP level and ESR are well–known and widely used markers for inflammation in the outpatient clinic. The numeric value of ESR can change according to the fibrinogen or immunoglobulin level; and the size, shape, and number of erythrocytes affects the ESR. These factors may decrease the usefulness of the ESR as an inflammatory indicator. The ESR increases in 1 or 2 weeks after initiation of an inflammatory reaction, but its range of variation is usually narrow. The serum level of CRP shows a sharp increase simultaneously that parallels the ESR but is not influenced by anemia, polycythemia, macrocytosis, or hyperimmunoglobulinemia where the ESR is increased. The level of CRP is often measured in cases of inflammatory disorders for monitoring a course and an effect of therapy (3). For these reasons, the ESR seldom shows a significant correlation with acute mucositis, whereas there was a significant relationship between the CRP level and mucosal reaction in our study. It is difficult to choose an appropriate scale for determining the grade of acute mucositis objectively in head–and–neck cancer patients. The World Health Organization classification has been a commonly used scale in radiation oncology and is similar to the acute mucosal toxicity criteria of the Radiation Therapy Oncology Group (RTOG). Other scales such as the European Organization for Research and Treatment of Cancer (EORTC) scale and the Southwest Oncology Group (SWOG) scale have been used (10). The NCI CTC version 2.0 has replaced the previous NCI CTC and the RTOG acute radiation morbidity scoring criteria, and has provided improvement in the evaluation and grading of acute mucositis caused by radiation. However, this grading system is occasionally ambiguous for classifying the grade accurately and for predicting the course of mucositis. In some diseases such as rheumatoid arthritis, serial measurements of the CRP level have a prognostic value (11). We made an effort to find out the statistically significant absolute level of CRP corresponding to Grade 2 or Grade 3 mucositis but could not determine it. We demonstrated that the CRP level increased in the course of fractionated irradiation and decreased after radiotherapy, and showed that the change of the mean CRP level was correlated with the progression of the mean grade of mucositis. Nevertheless, taking the serial
397
CRP levels into account, evaluating the patient’s mucosal reactions during or after radiotherapy is probably helpful to provide further information on the course of radiation– induced mucositis. The evaluation, management, and prevention of acute mucositis is a challenge in the treatment of head–and–neck cancer with radiation therapy. This is more important with the use of recent radiotherapy protocols such as hyperfractionation, the simultaneously integrated boost technique, and concurrent chemoradiotherapy. In this study, the IMRT was used in radiation treatment for all patients, and the patients treated with the CCRT protocol were all excluded. Given the use of IMRT and exclusion of CCRT cases, the most severe cases were of Grade 3 mucositis and there were no cases of Grade 4 mucositis. With the use of a conventional (two–dimensional) radiotherapy technique or CCRT protocol, there may be more Grade 3 or 4 mucositis and possibly a more significant correlation between CRP level and severity of mucositis. There was a significant correlation between acute mucositis and CRP level in this study, even though the results were obtained from only 40 patients and using an uncomplicated statistical approach. These findings do not indicate that the level of CRP always represents the grade of radiation– induced mucositis exactly, as the CRP level is also affected by various unknown factors or conditions such as secondary infection, dental problems, radiation dermatitis, or concurrent therapy. Using IMRT technique, however, we planned to restrict the skin dose within its tolerance dose. Every patient was sent to a dental clinic for preradiotherapy dental care. When the need arose, extractions or other invasive dental procedures were performed in 2 to 4 weeks before the beginning of radiotherapy. No patient was treated by the concurrent chemoradiotherapy protocol. Secondary infection including fungal infection at the oropharyngeal area can be induced by radiation–induced mucositis. Therefore we considered that radiation–induced inflammatory mucosal reaction was likely to be a major factor inducing the rise of CRP levels in this study. In addition, there is some doubt as to whether we could readily apply these results to an individual patient. It is very difficult to evaluate and to show the statistical correlation between change of CRP level and acute radiation–induced mucositis in all individual cases simultaneously, and using mean values of APR levels and grade of mucositis involves a lot of patient–to–patient variation. In conclusion, we need to carry out further research in the near future so that we obtain more concrete and individualized information. We plan to evaluate other factors related to radiation–induced mucositis, such as radiation technique and schedule, irradiated target area and its volume, concurrent medicine and therapy, and other APRs.
REFERENCES 1. Vera–Llonch M, Oster G, Hagiwara M, Sonis S. Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 2006;106:329–336.
2. Bensadoun RJ, Magne N, Marcy PY, Demard F. Chemotherapy– and radiotherapy–induced mucositis in head and neck cancer patients: New trends in pathophysiology, prevention
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3. 4. 5.
6. 7.
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and treatment. Eur Arch Otorhinolaryngol 2001;258:481– 487. Gabay C, Kushner I. Acute–phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340: 448–454. Cengiz M, Akbulut S, Atahan IL, Grigsby PW. Acute phase response during radiotherapy. Int J Radiat Oncol Biol Phys 2001; 49:1093–1096. Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: Version 2.0. An improved reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000;47:13–47. Koc M, Taysi S, Sezen O, Bakan N. Levels of some acute–phase proteins in the serum of patients with cancer during radiotherapy. Biol Pharm Bull 2003;26:1494–1497. Agroyannis B, Dardoufas C, Vitoratos N, et al. Changes of serum transferrin and ceruloplasmin after radiation therapy in
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8. 9. 10.
11.
women with cervical or uterine carcinoma. Clin Exp Obstet Gynecol 1994;21:24–27. Agroyannis B, Kouvaris J, Tzanatos H, et al. Influence of radiation treatment on serum transferrin and tumor necrosis factor– alpha. Anticancer Res 1992;12:1757–1759. Tang JT, Yamazaki H, Nishimoto N, et al. Effect of radiotherapy on serum level of interleukin 6 in patients with cervical carcinoma. Anticancer Res 1996;16:2005–2008. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemothreapy: A systematic literature review. Radiother Oncol 2003;66:253–262. van Leeuwen MA, van der Heijde DMFM, van Rijswijk MH, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis: A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants. J Rheumatol 1994;21:425–429.
doi:10.1016/j.ijrobp.2008.11.012
CLINICAL INVESTIGATION
Head and Neck
C–REACTIVE PROTEIN LEVELS AND RADIATION–INDUCED MUCOSITIS IN PATIENTS WITH HEAD–AND–NECK CANCER YONGKAN KI, M.D.,* WONTAEK KIM, M.D.,*y JIHO NAM, M.D.,* DONGHYUN KIM, M.D.,* DAHL PARK, PH.D.,* AND DONGWON KIM, M.D.*y * Department of Radiation Oncology, Pusan National University School of Medicine, and y Medical Research Institute, Pusan National University, Busan, Korea Purpose: To evaluate the relationship between C–reactive protein (CRP) levels or the erythrocyte sedimentation rate (ESR) and the grade of acute radiation–induced mucositis in patients with head–and–neck cancer. Methods and Materials: This study was performed in 40 patients who received intensity–modulated radiation therapy as a radical treatment of primary laryngo–pharyngeal cancer. Serum CRP level and ESR were initially checked on the day of radiotherapy simulation and were measured every week during the irradiation schedule and two times biweekly after radiotherapy. Mucosal reactions were evaluated by radiation oncologists on days of blood sampling. Results: The distribution of the most severe mucositis was Grade I mucositis in 10% of the patients, Grade II in 60% of the patients and Grade III in 30% of the patients. Statistical analysis indicated a significant rise in the CRP level (p < 0.001) according to radiation fraction number and grade of mucositis. A change of the mean CRP level was correlated with progression of mean grade of mucositis according to fraction number. The ESR did not show any statistically significant relationship with radiotherapy fraction number and grade of acute mucositis. Conclusions: There was a significant correlation between the presence of acute mucositis and CRP level in this study. The CRP level could be conveniently determined along with evaluation of mucosal reactions during or after radiotherapy to provide further information on radiation–induced mucositis. Ó 2009 Elsevier Inc. C–reactive protein, Erythrocyte sedimentation rate, Intensity–modulated radiation therapy, Acute mucositis, Head–and–neck cancer.
INTRODUCTION
induced mucositis. These factors, however, provide little information to predict the course (or the degree) of acute mucositis. Acute phase reactants (APRs) are widely used clinical indicators of the inflammatory and immunologic reactions induced by injury or infection. The level of C–reactive protein (CRP), a well–studied APR, and the erythrocyte sedimentation rate (ESR) can be measured easily in the outpatient clinic as direct and quantitative markers for inflammatory activity (3). Cengiz et al. (4) showed significant rises in the ESR and CRP levels at the end of radiotherapy to the pelvic–paraaortic field. These investigators also attempted to determine whether a rise in APR was correlated with acute and late radiation morbidity (radiation enteritis). However, there was no correlation between the clinical severity of acute and chronic radiation enteritis and APR rise. Nevertheless, it would be useful for radiation oncologists to assess radiation– induced mucositis with changes in APR. We evaluated the
One of the most common complications of radiotherapy for patients with head–and–neck cancer is acute mucositis of the upper digestive tract. Severe mucositis usually causes patients swallowing difficulty and local pain, which affects compliance with radiotherapy. A previous report noted undesired interruption of radiation therapy because of moderate to severe mucositis (1). Oncologists thus need to consider the appearance and change in grade of radiation–induced mucositis. There are many treatment–related findings, widely known as risk factors for acute oral mucositis, which include age, gender, body mass index, alcohol use, tobacco use, oral hygiene, stage of disease, white blood cell count, salivary rate, and normal flora of the mouth (2). Particularly as for radiotherapy–related factors, the dose per fraction, total dose, overall treatment duration, and fractionation schedule are able to influence the occurrence and severity of radiation–
Acknowledgment—This study was supported by Medical Research Institute Grant (2006–49), Pusan National University. Received Aug 29, 2008, and in revised form Oct 27, 2008. Accepted for publication Nov 5, 2008.
Reprint requests to: Wontaek Kim, M.D. Department of Radiation Oncology, Pusan National University School of Medicine, 1–10, Ami–dong, Seo–gu, Busan, Korea. Tel: 82–51–240–7383; Fax: 82–51–248–5747; E-mail: [email protected] Conflict of interest: none. 393
I. J. Radiation Oncology d Biology d Physics
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relationship between change in serum CRP levels and ESR and the course or degree (i.e., severity) of acute radiation– induced mucositis in patients who underwent radiation therapy for laryngo–pharyngeal cancer.
Volume 75, Number 2, 2009
method, using Modular E170 (Roche Diagnostics, Mannheim, Germany). A capillary microphotometer method was used for determination of the ESR by TEST1 (ALIFAX, Petrarca, Italy).
Analysis of acute mucositis METHODS AND MATERIALS Patients This study was designed to enroll primary laryngo–pharyngeal cancer patients who received whole–neck radiotherapy as a radical treatment between October 2005 and December 2006. The primary sites of cancer were the oropharynx, hypopharyx, supraglottis, and glottis. Clinical stages of all cases were classified according to the American Joint Committee on Cancer staging system (sixth edition) using a physical examination and imaging study. Some patients on a concurrent chemoradiotherapy (CCRT) protocol were excluded to rule out the impact of chemotherapy on acute phase reactions and symptomatic mucositis. Informed consent was obtained from all patients. This trial protocol was approved by the Institutional Review Board of our hospital.
Mucosal reactions on the irradiated field, especially the posterior aspect of the tongue and most parts of the oropharynx, were examined and described on days of blood sampling during and after radiotherapy. Acute mucositis was evaluated grossly and endoscopically by 1 radiation oncologist according to the use of the National Cancer Institute Common Toxicity Criteria (NCI CTC, version 2.0) and was confirmed by a second radiation oncologist. Each evaluation was independent. In the case that the 2 observers evaluated the grade of mucositis differently in the same patient, the higher grade was chosen. The NCI CTC for acute mucositis from radiation are the following: Grade 0, no mucositis; Grade 1, erythema of the mucosa; Grade 2, a patchy reaction #1.5 cm in diameter and noncontiguous; Grade 3, a confluent pseudomembranous reaction with contiguous patches generally greater than 1.5 cm in diameter; Grade 4, necrosis or deep ulceration including bleeding not induced by minor trauma or abrasion (5).
Radiotherapy Radiotherapy was performed with a seven–field intensity–modulated radiation therapy (IMRT) technique. Virtual simulation using computed tomography (CT) simulation and inverse radiotherapy planning were conducted to obtain conformal dose distribution over the primary tumor sites and cervical lymphatic systems. Six– megavoltage photon beams generated from a linear accelerator (Clinac 21–EX, Varian Medical Systems, Palo Alto, CA) and a dynamic multi–leaf collimator were using to deliver the intensity–modulated beam to complicated targets. The treatment targets were divided into three parts including Clinical Target Volume 1 (CTV1), Clinical Target Volume 2 (CTV2), and Clinical Target Volume 3 (CTV3). The primary tumor and enlarged lymph nodes, including a safety margin, denoted as CTV1. The boundary of CTV2 was the anatomical compartment and adjacent lymphatic systems embracing CTV1. The CTV3 was determined as the area that received elective radiation. The simultaneous integrated boost (SIB) technique was applied to administer different doses to each target. The total radiation dose was 70.0 to 74.2 Gy in 35 fractions to CTV1, 63.0 to 66.5 Gy to CTV2, and 56.0 to 59.5 Gy to CTV3. More than 54 Gy was planned to be delivered to clinically significant cervical lymph node levels such as Level II, III, IV, and V. The Level Ib lymphatic area was occasionally irradiated with more than 50 Gy. Most of the oral mucosa and some of the oropharyngeal mucosa in all patients were delineated, and the 10% and 50% volumes of these areas were constrained to receive a dose of less than 60 Gy and 40 Gy, respectively. Other important organs at risk such as the spinal cord, brainstem, and superficial lobes of the parotid glands were also contoured and were planned to receive less than 44 Gy, 50 Gy, and 20 Gy, respectively.
Analysis of CRP level and ESR Serum CRP levels and ESR were initially checked on the day of CT simulation. Subsequently the serum CRP level and ESR were measured every week during the irradiation schedule and two times biweekly after the end of radiotherapy. Blood sampling was performed approximately 1 h after irradiation. The start of radiotherapy was delayed 2 to 3 weeks for 8 patients who had received several cycles of induction chemotherapy so as to reduce the indefinite side effects of the systemic cytotoxic agents. The level of CRP was measured with an electrochemiluminescence immunoassay
Statistical analysis The Kruskall–Wallis test was used for the analysis of the relationship between changes in CRP levels and ESR and the grade of radiation–induced mucositis. Statistical analysis for the correlation between the radiotherapy fraction numbers and the serum concentration of CRP or the ESR or the grade of mucositis was determined by use of the paired t test. Mean values of the APR level and grade of mucositis according to the fraction numbers were used, instead of each maximum value, to evaluate the positive correlation. Statistical analyses were performed with SPSS software (SPSS Inc., Chicago, IL). A p value of less than 0.05 was regarded as statistically significant.
RESULTS A total of 52 patients were initially included in this study. However, 4 patients were unable to complete their whole course of radiotherapy in 80 days because of personal problems, and 8 patients refused sequential blood samplings in the course of radiotherapy. Ultimately, 40 patients underwent the radiation therapy schedules. The patients underwent periodic testing of CRP levels and ESR, and mucosal reactions were evaluated. Characteristics of the patients are summarized in Table 1. All of the patients were diagnosed with one or Table 1. Characteristics of the study patients Characteristic
Patients (n) (N = 40)
Median age, y (range) Male:Female Site Oropharynx Hypopharynx Supraglottis Glottis AJCC Stage III IVA IVB
61 (47–69) 32:8
%
14 8 10 8
35 20 25 20
6 32 2
15 80 5
Abbreviation: AJCC = American Joint Committee on Cancer.
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Table 2. Mean C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR) according to radiotherapy schedules (fraction numbers) CRP level (mg/dl)
ESR (mm)
Radiotherapy schedule
Mean
SD
Mean
SD
Pre-RT Fraction 5 Fraction 10 Fraction 15 Fraction 20 Fraction 25 Fraction 30 Fraction 35 Post-RT Week 2 Post-RT Week 4
0.26 0.27 0.84 0.87 1.80 1.93 2.08 2.12 1.07 0.74
0.19 0.37 1.51 1.10 2.77 2.09 2.45 2.95 0.23 0.12
44 43 32 45 43 48 49 70 48 50
28 28 16 18 11 17 19 42 15 2
Abbreviations: Pre-RT = before radiotherapy; Post-RT = after radiotherapy; SD = standard deviation.
more cervical lymph nodes; there were no metastases to the submental lymph nodes. The mean duration of radiotherapy was 50 days (range, 45–62 days). Acute radiation–induced mucositis developed in all patients, and the distribution of the most severe mucosal reactions during the radiotherapy schedule were Grade I mucositis in 10% of the patients, Grade II mucositis in 60%, and Grade III mucositis in 30%; there was no Grade IV mucositis. The mean grade of mucositis as a function of radiation fraction number increased significantly during the radiotherapy schedule (p < 0.001; Fig. 3). The CRP levels showed a significant increase by the 15th radiotherapy fraction. Variations in the CRP level and ESR during irradiation are shown in Table 2. Mean CRP levels increased significantly during the course of fractionated radiotherapy and decreased after radiotherapy (p < 0.001); mean CRP level and ESR in accordance with the grade of mucositis are shown in Table 3. Statistical analysis demonstrated a significant rise in the mean value of the CRP level (p < 0.001) according to the fraction number and the grade of mucositis (Figs. 1 and 2). Figure 3 shows that the change in mean level of CRP was correlated with progression of the mean grade of mucositis according to the fraction number. As the mean grade of mucositis increased or decreased, the mean CRP concentration changed nearly simultaneously (correlation coefficient = 0.544, p <0.001).
Fig. 1. Changes in C–reactive protein (CRP) levels (95% confidence interval [95% CI]) according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
Hemoglobin levels were also checked, as ESR could vary with the concentration of hemoglobin; however, there was no significant change in the hemoglobin level during irradiation. The ESR did not show any statistically significant relationship with the fraction number of radiotherapy and grade of acute mucositis (p = 0.58) (Figs. 4 and 5). Mean ESR varied little with fraction number (p = 0.67). Induction chemotherapy had little effect on mean CRP. The coefficient of correlation between the group treated with induction chemotherapy
Table 3. Mean C-reactive protein (CRP) levels and erythrocyte sedimentation rates (ESR) according to grade of acute radiation-induced mucositis CRP level (mg/dl)
ESR (mm)
Grade
Mean
SD
Mean
SD
0 1 2 3
0.27 0.64 1.70 3.07
0.37 0.72 2.30 3.21
43 40 50 40
26 25 24 9
Fig. 2. Changes in C–reactive protein (CRP) levels (95% confidence interval [95% CI]) according to grade of acute mucositis.
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Fig. 3. Mean C–reactive protein (CRP) levels and mean grade of acute mucositis determined according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
and the group without induction therapy was 0.828 (p = 0.006). DISCUSSION Vera–Llonch et al. (1) reported that the radiation–induced mucositis developed in 80% of head–and–neck cancer patients and that a severe mucosal reaction occurred in 29% of patients. There have been several trials to determine a correlation between radiation–induced inflammation and levels of APR. Some studies have demonstrated that radiation might be a cause of a significant change in APRs. One study
Fig. 4. Changes in erythrocyte sedimentation rate (ESR) (95% confidence interval [95% CI]) according to radiotherapy fraction number. post–RT = after radiotherapy; wk = week.
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Fig. 5. Changes in erythrocyte sedimentation rate (ESR) (95% confidence interval [95% CI]) according to grade of acute mucositis.
showed that radiation decreased the serum transferrin level and increased the level of serum CRP, ferritin, and ceruloplasmin in cancer of the digestive tract, including head– and–neck cancer (6). Another study determined that the level of transferrin decreased, whereas the level of tumor necrosis factor–a and ceruloplasmin increased during radiotherapy for gynecologic cancer (7, 8). Tang et al. (9) observed that pelvic radiotherapy did not change the level of CRP, whereas Cengiz et al. (4) reported that pelvic irradiation in patients with gynecologic cancer was associated with an increase in CRP level and ESR. Based on these findings, it is presumed that radiation exposure has caused acute radiation–induced inflammatory reactions, leading to an increase in APR levels. Even though no definite evidence indicating a significant correlation between acute enteritis and APR levels in the study by Cengiz et al. was reported, we assumed that acute radiation–induced mucositis in the head–and–neck area may have a significant correlation with APR level. Bowel toxicities were recorded and were scored according to patient subjective symptoms and clinical signs, however, oral or oropharyngeal mucositis could be diagnosed and be evaluated by direct examination of the patients. In addition, acute mucositis at the head and neck area occurred frequently in most patients who had undergone irradiation, and the symptoms were relatively severe. More concrete supplementary data or information on radiation–induced inflammation may provide details on the relationship with APRs. We wished to evaluate the severity of radiation–induced mucositis and the change in the CRP level and ESR in the head–and–neck cancer patients, and also aimed to determine a possible correlation between serum levels of APRs and the course of mucositis. No significant clinical relation with the radiation fraction number and the severity of mucositis was correlated with a change in the
CRP and radiation–induced mucositis d Y. KI et al.
ESR in this study. The serum level of CRP showed an increasing trend with fraction number, which indicated a statistically significant correlation between the cumulative radiation dose and grade of acute radiation–induced mucositis. Our results also showed that the mean value of CRP levels increased similarly with the mean grade of mucositis during the course of fractionated radiotherapy. Simple measurement of the serum concentration of APR is possibly less sensitive and less specific for determining the inflammatory mechanism of acute mucositis and its distinct severity. Nevertheless, the CRP level and ESR are well–known and widely used markers for inflammation in the outpatient clinic. The numeric value of ESR can change according to the fibrinogen or immunoglobulin level; and the size, shape, and number of erythrocytes affects the ESR. These factors may decrease the usefulness of the ESR as an inflammatory indicator. The ESR increases in 1 or 2 weeks after initiation of an inflammatory reaction, but its range of variation is usually narrow. The serum level of CRP shows a sharp increase simultaneously that parallels the ESR but is not influenced by anemia, polycythemia, macrocytosis, or hyperimmunoglobulinemia where the ESR is increased. The level of CRP is often measured in cases of inflammatory disorders for monitoring a course and an effect of therapy (3). For these reasons, the ESR seldom shows a significant correlation with acute mucositis, whereas there was a significant relationship between the CRP level and mucosal reaction in our study. It is difficult to choose an appropriate scale for determining the grade of acute mucositis objectively in head–and–neck cancer patients. The World Health Organization classification has been a commonly used scale in radiation oncology and is similar to the acute mucosal toxicity criteria of the Radiation Therapy Oncology Group (RTOG). Other scales such as the European Organization for Research and Treatment of Cancer (EORTC) scale and the Southwest Oncology Group (SWOG) scale have been used (10). The NCI CTC version 2.0 has replaced the previous NCI CTC and the RTOG acute radiation morbidity scoring criteria, and has provided improvement in the evaluation and grading of acute mucositis caused by radiation. However, this grading system is occasionally ambiguous for classifying the grade accurately and for predicting the course of mucositis. In some diseases such as rheumatoid arthritis, serial measurements of the CRP level have a prognostic value (11). We made an effort to find out the statistically significant absolute level of CRP corresponding to Grade 2 or Grade 3 mucositis but could not determine it. We demonstrated that the CRP level increased in the course of fractionated irradiation and decreased after radiotherapy, and showed that the change of the mean CRP level was correlated with the progression of the mean grade of mucositis. Nevertheless, taking the serial
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CRP levels into account, evaluating the patient’s mucosal reactions during or after radiotherapy is probably helpful to provide further information on the course of radiation– induced mucositis. The evaluation, management, and prevention of acute mucositis is a challenge in the treatment of head–and–neck cancer with radiation therapy. This is more important with the use of recent radiotherapy protocols such as hyperfractionation, the simultaneously integrated boost technique, and concurrent chemoradiotherapy. In this study, the IMRT was used in radiation treatment for all patients, and the patients treated with the CCRT protocol were all excluded. Given the use of IMRT and exclusion of CCRT cases, the most severe cases were of Grade 3 mucositis and there were no cases of Grade 4 mucositis. With the use of a conventional (two–dimensional) radiotherapy technique or CCRT protocol, there may be more Grade 3 or 4 mucositis and possibly a more significant correlation between CRP level and severity of mucositis. There was a significant correlation between acute mucositis and CRP level in this study, even though the results were obtained from only 40 patients and using an uncomplicated statistical approach. These findings do not indicate that the level of CRP always represents the grade of radiation– induced mucositis exactly, as the CRP level is also affected by various unknown factors or conditions such as secondary infection, dental problems, radiation dermatitis, or concurrent therapy. Using IMRT technique, however, we planned to restrict the skin dose within its tolerance dose. Every patient was sent to a dental clinic for preradiotherapy dental care. When the need arose, extractions or other invasive dental procedures were performed in 2 to 4 weeks before the beginning of radiotherapy. No patient was treated by the concurrent chemoradiotherapy protocol. Secondary infection including fungal infection at the oropharyngeal area can be induced by radiation–induced mucositis. Therefore we considered that radiation–induced inflammatory mucosal reaction was likely to be a major factor inducing the rise of CRP levels in this study. In addition, there is some doubt as to whether we could readily apply these results to an individual patient. It is very difficult to evaluate and to show the statistical correlation between change of CRP level and acute radiation–induced mucositis in all individual cases simultaneously, and using mean values of APR levels and grade of mucositis involves a lot of patient–to–patient variation. In conclusion, we need to carry out further research in the near future so that we obtain more concrete and individualized information. We plan to evaluate other factors related to radiation–induced mucositis, such as radiation technique and schedule, irradiated target area and its volume, concurrent medicine and therapy, and other APRs.
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