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Severity of oral mucositis correlates with the response of oral cancer to preoperative radiochemotherapy
Int. J. Oral Maxillofac. Surg. 2005; 34: 642–645 doi:10.1016/j.ijom.2005.03.007, available online at http://www.sciencedirect.com
Clinical Paper Head & Neck Oncology
Severity of oral mucositis correlates with the response of oral cancer to preoperative radiochemotherapy
T. Ikebe1,2, K. Seki2, S. Nakamura2, Y. Takenoshita2, H. Nakayama1, M. Shinohara1, K. Shirasuna2 1 Department of Oral and Maxillofacial Surgery, Sensory and Motor Organ Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto 860-8556, Japan; 2 Section of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
T. Ikebe, K. Seki, S. Nakamura, Y. Takenoshita, H. Nakayama, M. Shinohara, K. Shirasuna: Severity of oral mucositis correlates with the response of oral cancer to preoperative radiochemotherapy. Int. J. Oral Maxillofac. Surg. 2005; 34: 642–645. # 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Oral mucositis is a dose-limiting toxic effect of radiotherapy and chemotherapy on oral cancer. The purpose of the present study is to assess the relationship between tumor response and oral mucositis in preoperative radiochemotherapy for oral cancer retrospectively. Fifty-four cases of oral squamous cell carcinoma were treated with concurrent radiochemotherapy prior to surgery. When oral mucositis was evaluated with the WHO scale, severe oral mucositis (Grades 3 and 4) developed in 22 cases (41%). A more than 50% reduction in tumor size was clinically observed in 38 cases (70%). From histopathological analysis of the surgical specimens all tumor cells observed appeared to be non-viable in 16 cases (29%). The cases with Grade 1, Grade 2, Grade 3 and Grade 4 oral mucositis included 33%, 62%, 85% and 89% of clinical good-response cases and 0%, 24%, 31% and 55% of histopathological good-response cases, respectively. This retrospective study suggests that severe oral mucositis promises a good response of oral squamous cell carcinoma to radiochemotherapy.
Accepted for publication 15 March 2005 Available online 24 May 2005
Radiation and chemotherapy are usual methods for the treatment of oral cancer. Oral mucositis is one of the common toxic complications associated with these therapies. In particular, radiotherapy for oral cancer inevitably induces oral mucositis since normal oral mucosa around the tumor is directly exposed to radiation. Non-keratinized surfaces, such as buccal and labial mucosa, oral floor, soft palate and the ventral surface of the tongue, are most severely affected in radio-
in decreased cell regeneration, epithelial atrophy and mucosal thinning, and mucositis10. In spite of the common pathological mechanism of mucositis, however, the severity of oral mucositis varies from patient to patient, suggesting that there exist intrinsic factors which determine the susceptibility of mucosal cells to radiation or anti-cancer drugs. The levels of such putative factors may be different in each patient. In our hospital, the patients with oral cancer are preoperatively treated with
0901-5027/060642+04 $30.00/0
therapy and chemotherapy. Erythema is an initial manifestation followed by the development of white desquamative patches, which lead to the formation of pseudomembrane and ulceration9,10. Oral mucositis induces oral pain, impairs oral functions such as eating and swallowing, and damages quality of life. Radiation and anti-cancer drugs damage the dividing cells most effectively and induce the apoptosis of progenitor cells in normal mucosa, which in turn results
# 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
643
Oral mucositis and tumor response concurrent radiation and chemotherapy, mainly bleomycin, and this regimen rarely induces serious systemic complications such as pulmonary fibrosis, with the exception of oral mucositis6. Although almost all patients suffer from oral mucositis during treatment, we have often noted that tumors of the oral cavity are reduced more extensively in patients with severe oral mucositis than in those with only the mild condition. This experience suggests that severe mucositis is related to tumor reduction in radiochemotherapy. If the intrinsic factors determining sensitivity to radiochemotherapy are shared between normal mucosal cells and malignant tumor cells in the same patients, radiation or anticancer drugs will damage normal cells and tumor cells equally. The present study was thus designed to confirm whether severity of oral mucositis actually correlates with the tumor response to radiochemotherapy in oral squamous cell carcinoma. Materials and methods Patients
From 1992 to 1999, 54 patients diagnosed as having squamous cell carcinoma of the oral cavity were studied retrospectively. Their clinical data are shown in Table 1. All the patients were treated concurrently with 2250 cGy radiation (150 cGy/fraction, one fraction/day, for 15 days) plus 110 mg bleomycin (10 mg/day, for 11 days) prior to surgery. Patients treated with calboplatin or 5-FU coupled with radiation in the study period were excluded. Fifty-one patients with oral mucositis above Grade 1 were treated with steroid powder (beclometasone dipropionate) and an oral rinse containing lidoTable 1. Patient characteristics Gender Female Male Age (years) Mean (range)
21 33
caine, sodium gualenate and enzymes (fibrinolysin and deoxyribonuclease) 1 week after radiochemotherapy started. Such treatments relieved the symptoms of oral mucositis, but did not interfere with the grading of oral mucositis. Oral mucositis developed in all the patients, but never caused postponement of the date of surgery. Tumors in all cases were ablated radically.
Statistical method
Clinical tumor response assessment
Oral mucositis developed in all 54 patients. On average, the onset of oral mucositis was observed at Day 12 (radiation dose 1320 cGy) after radiochemotherapy started, and symptoms reached their worst at Day 22 (2150 cGy), when the grade of mucositis was evaluated. Oral mucositis subsided 13 days after the end of radiochemotherapy. There were no cases in which surgery was deferred because of oral mucositis.
A week after the end of radiochemotherapy, the effects of preoperative radiochemotherapy on tumor volume were clinically evaluated into four categories: complete response (CR), partial response (PR), no change (NC) and progressive disease (PD). CR was defined as the complete disappearance of measurable disease; PR as more than 50% reduction in the sum of the products of the perpendicular diameters; NC as no significant change (<25% increase or decrease) in tumor size; and PD as an increase in the measured lesion by >25%. Histopathological tumor response assessment
After surgery, the histological response of tumors to preoperative radiochemotherapy was evaluated in the surgical specimens according to the histopathological criteria of SHIMOSATO et al.8, as follows: Grade I, tumor structures were not obliterated; Grade IIa, obliteration of tumor structures was mild and viable tumor cells were observed in more than 25% of the lesion; Grade IIb, obliteration of tumor structures was severe and viable tumor cells were observed in less than 25% of the lesion; Grade III, only non-viable tumor cells were present; Grade IV, tumor cells were not observed and tumor was replaced with necrotic tissue, granulation tissue or scar. Scoring of oral mucositis
62.5 (46–86)
Tumor localization Lower gum Tongue Upper gum Oral floor Buccal mucosa Palate
21 10 8 7 5 3
Stage I II III IV
2 16 14 22
Total
54
Severity of oral mucositis was evaluated clinically according to the WHO toxicity score1,7, in which Grade 1 = soreness and erythema; Grade 2 = erythema, ulcer, can eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible. We scored oral mucositis every day until mucositis subsided to Grade 1, and determined its Grade when the symptoms of mucositis were severest. Surgery was performed 2–3 weeks after the end of radiochemotherapy when oral mucositis subsided at least below Grade 2.
Statistical analyses of the correlation between severity of oral mucositis and degree of clinical/histopathological tumor response were performed using x2 tests. The significance level was set at P < 0.05. Results Time course of oral mucositis
Scoring of oral mucositis
Of the 54 patients studied, Grade 4 mucositis, in which tube feeding or intravenous hyperalimentation is undertaken, was seen in nine (17%), Grade 3 mucositis in 13 (24%), Grade 2 mucositis in 29 (54%), and Grade 1 mucositis in three (5%) (Table 2). Clinical and histopathological assessment of tumor response to preoperative radiochemotherapy
The preoperative concurrent radiation and chemotherapy reduced the clinical size of tumors, resulting in six cases (11%) of CR, 32 cases (59%) of PR, 15 cases (28%) of NC, and one case (2%) of PD (Table 3). In the histopathological assessment of response of tumor, 10 cases (18%) were regarded as Grade IV and six cases (11%) as Grade III (Table 3), meaning that no histopathologically viable cells were found in the specimens, suggesting that the preoperative therapy had obliterated the tumor cells. Twenty-three cases (43%) were classified as Grade IIb, where more than 75% of tumor cells appeared to be dead in the resected specimens (Table 3). Table 2. Severity of oral mucositis (WHO)* Grade Grade Grade Grade Grade
0 1 2 3 4
Total *
See materials and methods.
0 3 29 13 9
(0%) (5%) (54%) (24%) (17%)
54 cases
644
Ikebe et al.
Table 3. Tumor response to neoadjuvant radiochemotherapy Clinical tumor response* CR PR NC PD
6 32 15 1
Total
54 cases
Histopathological response* Grade I Grade IIa Grade IIb Grade III Grade IV
0 15 23 6 10
Total
54 cases
*
(11%) (59%) (28%) (2%)
(0%) (28%) (43%) (11%) (18%)
See materials and methods.
Relationship between oral mucositis grade and tumor response
Tables 4 and 5 show the comparison of oral mucositis grade with clinical and histopathological tumor response to the
radiochemotherapy, respectively. The results of Tables 4 and 5 are summarized in Table 6. In clinical response, 89% of the cases with Grade 4 mucositis corresponded to the cases of PR or CR, while only 33% of the cases with Grade 1 mucositis showed PR or CR (Table 6). Statistically, the severity of oral mucositis correlated with the degree of clinical tumor response (P < 0.05) (Table 4). Likewise, all the tumor cells observed in the specimen appeared to be histopathologically dead (Grades III and IV) after preoperative therapy in 55% of the cases with Grade 4 mucositis, 31% with Grade 3 mucositis, 24% with Grade 2 mucositis and 0% with Grade 1 mucositis (Table 6). The grade of histopathological tumor response also significantly correlated to the severity of oral mucositis (P < 0.05) (Table 5). In contrast, only four cases (7%) of severe mucositis had less tumor reduction and seven cases (13%) with mild mucositis showed extensive tumor death. These data suggest that the severer the
Table 4. Relationship between oral mucositis and clinical tumor response* Severity of oral mucositis Clinical response CR PR NC PD Total *
Grade 1
Grade 2
Grade 3
Grade 4
Total
0 1 2 0
2 16 10 1
2 9 2 0
2 6 1 0
6 32 15 1
3
29
13
9
54
x2 test: P < 0.05.
Table 5. Relationship between oral mucositis and histopathological tumor response* Severity of oral mucositis Histopathological tumor response Grade Grade Grade Grade Grade
I IIa IIb III IV
Total *
Grade 1
Grade 2
Grade 3
Grade 4
Total
0 1 2 0 0
0 10 12 1 6
0 3 6 2 2
0 1 3 3 2
0 15 23 6 10
3
29
13
9
54
2
x test: P < 0.05.
Table 6. Severity of oral mucositis in good tumor responders to neoadjuvant radiochemotherapy Good tumor responders Oral mucositis grade
CR + PR*
Grade Grade Grade Grade
1 18 11 8
1 2 3 4
(n = 3) (n = 29) (n = 13) (n = 9)
(33%) (62%) (85%) (89%)
Grades III + IV** 0 (0%) 7 (24%) 4 (31%) 5 (55%)
Data in parentheses in columns 2 and 3 express percentage in each grade of oral mucositis. * Clinical tumor response. ** Histopathological tumor response.
development of oral mucositis, the more the tumor cells were damaged by the concurrent radiochemotherapy. Discussion
In the present retrospective study, we found that the severity of oral mucositis correlated with clinical and histopathological tumor response to preoperative radiochemotherapy in oral squamous cell carcinoma. Both radiotherapy and chemotherapy induce oral mucositis as an unpleasant, adverse effect. Radiotherapy for oral cancer directly affects normal oral mucosa to give rise to oral mucositis. Combined with chemotherapy, where some anti-cancer drugs work as radiation sensitizers, radiation should more severely impair oral mucosa. However, some patients suffered from severe oral mucositis, while oral mucositis of others was mild, suggesting that the sensitivity of oral mucosa to radiochemotherapy is determined by such intrinsic factors as genes. Some of the genetic factors involved in the radiosensitivity of normal oral mucosa are likely to be shared with oral squamous cell carcinoma, as the present study showed that the response of oral cancer to radiochemotherapy correlated with the susceptibility of normal oral mucosa to the therapy in many cases. In addition, the radiosensitivity of normal skin fibroblasts is reported to correlate with that of squamous carcinoma cells in the same individual4. Because oral mucositis worsens quality of life, various methods of managing, treating and preventing oral mucositis have been reported5. Recently, an oral rinse, including such growth factors as granulocyte and granulocyte–macrophage colony-stimulating factors3 and keratinocyte growth factor11, which promote the restoration of damaged epithelial cells, has been applied to oral mucositis. However, in oral cancer, the topical application of growth factor may in fact stimulate the proliferation of tumor cells. We usually control the symptoms of oral mucositis with topical use of steroid and oral rinse containing lidocaine and proteases. Although steroid may increase the risk of infection in oral mucosa, it can also decrease the inflammatory reactions in the mucosa. Steroid is also reported to inhibit the production of the invasion-related proteases in oral cancer2. As oral mucositis is thought to be induced by inflammatory cytokines such as interleukin-1 and tumor necrosis factor a, which are released from mucosal tissues stressed by radiation and anti-cancer drugs10, anti-cytokine therapy
Oral mucositis and tumor response is expected to be an efficient method for reducing oral mucositis. Because the sample size was small in this study, we could not relate oral mucositis grade to tumor site and stage. Likewise, the severity of oral mucositis could not be compared with recurrence and survival rate. Moreover, it is uncertain whether the severity of mucositis is more related to the radiotherapy than the chemotherapy. Further study with a larger sample size is required to solve these problems. In conclusion, severe oral mucositis may promise a good response of oral squamous cell carcinoma to preoperative radiochemotherapy. References 1. ANONYMOUS. Handbook for Reporting Results of Cancer Treatment. Vol 48: WHO Offset Publication 1979: 15–22. 2. Beppu M, Ikebe T, Shirasuna K. The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin4, on NF-kB-mediated protease production by oral cancer. Biochim Biophys Acta 2002: 1586: 11–22.
3. Chi KH, Chen CH, Chan WK, Chow KC, Chen SY, Yen SH, Chao JY. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil and leucovorin chemotherapy. J Clin Oncol 1995: 13: 2620–2628. 4. Haikonen J, Rantanen V, Pekkola K, Kulmala J, Grenman R. Does skin fibroblast radiosensitivity predict squamous cancer cell radiosensitivity of the same individual? Int J Cancer 2003: 103: 784–788. 5. Mead GM. Management of oral mucositis associated with cancer chemotherapy. Lancet 2002: 359: 815–816. 6. Ozeki S, Okamoto M, Tashiro H, Jingu K. The effects of combined radiation and bleomycin therapy on the cervical lymph nodes metastasized from oral cancer. J Jpn Soc Cancer Ther 1986: 21: 664–670. 7. Parulekar W, Mackenzie R, Bjarnason G, Jordan RCK. Scoring oral mucositis. Oral Oncol 1998: 34: 63–71. 8. Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinomas. Jpn J Oncol 1971: 1: 19–35.
645
9. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998: 34: 39–43. 10. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004: 4: 277–284. 11. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre F, Sung EC, Blazar BR, Elhardt D, Chen M-G, Emmanouilides C. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004: 351: 2590–2598. Address: Tetsuro Ikebe Department of Oral and Maxillofacial Surgery Sensory and Motor Organ Sciences Faculty of Medical and Pharmaceutical Sciences Kumamoto University 1-1-1 Honjyo Kumamoto 860-8556 Japan Fax: +81 96 373 5286 E-mail: [email protected]
Clinical Paper Head & Neck Oncology
Severity of oral mucositis correlates with the response of oral cancer to preoperative radiochemotherapy
T. Ikebe1,2, K. Seki2, S. Nakamura2, Y. Takenoshita2, H. Nakayama1, M. Shinohara1, K. Shirasuna2 1 Department of Oral and Maxillofacial Surgery, Sensory and Motor Organ Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjyo, Kumamoto 860-8556, Japan; 2 Section of Oral and Maxillofacial Surgery, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
T. Ikebe, K. Seki, S. Nakamura, Y. Takenoshita, H. Nakayama, M. Shinohara, K. Shirasuna: Severity of oral mucositis correlates with the response of oral cancer to preoperative radiochemotherapy. Int. J. Oral Maxillofac. Surg. 2005; 34: 642–645. # 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved. Abstract. Oral mucositis is a dose-limiting toxic effect of radiotherapy and chemotherapy on oral cancer. The purpose of the present study is to assess the relationship between tumor response and oral mucositis in preoperative radiochemotherapy for oral cancer retrospectively. Fifty-four cases of oral squamous cell carcinoma were treated with concurrent radiochemotherapy prior to surgery. When oral mucositis was evaluated with the WHO scale, severe oral mucositis (Grades 3 and 4) developed in 22 cases (41%). A more than 50% reduction in tumor size was clinically observed in 38 cases (70%). From histopathological analysis of the surgical specimens all tumor cells observed appeared to be non-viable in 16 cases (29%). The cases with Grade 1, Grade 2, Grade 3 and Grade 4 oral mucositis included 33%, 62%, 85% and 89% of clinical good-response cases and 0%, 24%, 31% and 55% of histopathological good-response cases, respectively. This retrospective study suggests that severe oral mucositis promises a good response of oral squamous cell carcinoma to radiochemotherapy.
Accepted for publication 15 March 2005 Available online 24 May 2005
Radiation and chemotherapy are usual methods for the treatment of oral cancer. Oral mucositis is one of the common toxic complications associated with these therapies. In particular, radiotherapy for oral cancer inevitably induces oral mucositis since normal oral mucosa around the tumor is directly exposed to radiation. Non-keratinized surfaces, such as buccal and labial mucosa, oral floor, soft palate and the ventral surface of the tongue, are most severely affected in radio-
in decreased cell regeneration, epithelial atrophy and mucosal thinning, and mucositis10. In spite of the common pathological mechanism of mucositis, however, the severity of oral mucositis varies from patient to patient, suggesting that there exist intrinsic factors which determine the susceptibility of mucosal cells to radiation or anti-cancer drugs. The levels of such putative factors may be different in each patient. In our hospital, the patients with oral cancer are preoperatively treated with
0901-5027/060642+04 $30.00/0
therapy and chemotherapy. Erythema is an initial manifestation followed by the development of white desquamative patches, which lead to the formation of pseudomembrane and ulceration9,10. Oral mucositis induces oral pain, impairs oral functions such as eating and swallowing, and damages quality of life. Radiation and anti-cancer drugs damage the dividing cells most effectively and induce the apoptosis of progenitor cells in normal mucosa, which in turn results
# 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
643
Oral mucositis and tumor response concurrent radiation and chemotherapy, mainly bleomycin, and this regimen rarely induces serious systemic complications such as pulmonary fibrosis, with the exception of oral mucositis6. Although almost all patients suffer from oral mucositis during treatment, we have often noted that tumors of the oral cavity are reduced more extensively in patients with severe oral mucositis than in those with only the mild condition. This experience suggests that severe mucositis is related to tumor reduction in radiochemotherapy. If the intrinsic factors determining sensitivity to radiochemotherapy are shared between normal mucosal cells and malignant tumor cells in the same patients, radiation or anticancer drugs will damage normal cells and tumor cells equally. The present study was thus designed to confirm whether severity of oral mucositis actually correlates with the tumor response to radiochemotherapy in oral squamous cell carcinoma. Materials and methods Patients
From 1992 to 1999, 54 patients diagnosed as having squamous cell carcinoma of the oral cavity were studied retrospectively. Their clinical data are shown in Table 1. All the patients were treated concurrently with 2250 cGy radiation (150 cGy/fraction, one fraction/day, for 15 days) plus 110 mg bleomycin (10 mg/day, for 11 days) prior to surgery. Patients treated with calboplatin or 5-FU coupled with radiation in the study period were excluded. Fifty-one patients with oral mucositis above Grade 1 were treated with steroid powder (beclometasone dipropionate) and an oral rinse containing lidoTable 1. Patient characteristics Gender Female Male Age (years) Mean (range)
21 33
caine, sodium gualenate and enzymes (fibrinolysin and deoxyribonuclease) 1 week after radiochemotherapy started. Such treatments relieved the symptoms of oral mucositis, but did not interfere with the grading of oral mucositis. Oral mucositis developed in all the patients, but never caused postponement of the date of surgery. Tumors in all cases were ablated radically.
Statistical method
Clinical tumor response assessment
Oral mucositis developed in all 54 patients. On average, the onset of oral mucositis was observed at Day 12 (radiation dose 1320 cGy) after radiochemotherapy started, and symptoms reached their worst at Day 22 (2150 cGy), when the grade of mucositis was evaluated. Oral mucositis subsided 13 days after the end of radiochemotherapy. There were no cases in which surgery was deferred because of oral mucositis.
A week after the end of radiochemotherapy, the effects of preoperative radiochemotherapy on tumor volume were clinically evaluated into four categories: complete response (CR), partial response (PR), no change (NC) and progressive disease (PD). CR was defined as the complete disappearance of measurable disease; PR as more than 50% reduction in the sum of the products of the perpendicular diameters; NC as no significant change (<25% increase or decrease) in tumor size; and PD as an increase in the measured lesion by >25%. Histopathological tumor response assessment
After surgery, the histological response of tumors to preoperative radiochemotherapy was evaluated in the surgical specimens according to the histopathological criteria of SHIMOSATO et al.8, as follows: Grade I, tumor structures were not obliterated; Grade IIa, obliteration of tumor structures was mild and viable tumor cells were observed in more than 25% of the lesion; Grade IIb, obliteration of tumor structures was severe and viable tumor cells were observed in less than 25% of the lesion; Grade III, only non-viable tumor cells were present; Grade IV, tumor cells were not observed and tumor was replaced with necrotic tissue, granulation tissue or scar. Scoring of oral mucositis
62.5 (46–86)
Tumor localization Lower gum Tongue Upper gum Oral floor Buccal mucosa Palate
21 10 8 7 5 3
Stage I II III IV
2 16 14 22
Total
54
Severity of oral mucositis was evaluated clinically according to the WHO toxicity score1,7, in which Grade 1 = soreness and erythema; Grade 2 = erythema, ulcer, can eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible. We scored oral mucositis every day until mucositis subsided to Grade 1, and determined its Grade when the symptoms of mucositis were severest. Surgery was performed 2–3 weeks after the end of radiochemotherapy when oral mucositis subsided at least below Grade 2.
Statistical analyses of the correlation between severity of oral mucositis and degree of clinical/histopathological tumor response were performed using x2 tests. The significance level was set at P < 0.05. Results Time course of oral mucositis
Scoring of oral mucositis
Of the 54 patients studied, Grade 4 mucositis, in which tube feeding or intravenous hyperalimentation is undertaken, was seen in nine (17%), Grade 3 mucositis in 13 (24%), Grade 2 mucositis in 29 (54%), and Grade 1 mucositis in three (5%) (Table 2). Clinical and histopathological assessment of tumor response to preoperative radiochemotherapy
The preoperative concurrent radiation and chemotherapy reduced the clinical size of tumors, resulting in six cases (11%) of CR, 32 cases (59%) of PR, 15 cases (28%) of NC, and one case (2%) of PD (Table 3). In the histopathological assessment of response of tumor, 10 cases (18%) were regarded as Grade IV and six cases (11%) as Grade III (Table 3), meaning that no histopathologically viable cells were found in the specimens, suggesting that the preoperative therapy had obliterated the tumor cells. Twenty-three cases (43%) were classified as Grade IIb, where more than 75% of tumor cells appeared to be dead in the resected specimens (Table 3). Table 2. Severity of oral mucositis (WHO)* Grade Grade Grade Grade Grade
0 1 2 3 4
Total *
See materials and methods.
0 3 29 13 9
(0%) (5%) (54%) (24%) (17%)
54 cases
644
Ikebe et al.
Table 3. Tumor response to neoadjuvant radiochemotherapy Clinical tumor response* CR PR NC PD
6 32 15 1
Total
54 cases
Histopathological response* Grade I Grade IIa Grade IIb Grade III Grade IV
0 15 23 6 10
Total
54 cases
*
(11%) (59%) (28%) (2%)
(0%) (28%) (43%) (11%) (18%)
See materials and methods.
Relationship between oral mucositis grade and tumor response
Tables 4 and 5 show the comparison of oral mucositis grade with clinical and histopathological tumor response to the
radiochemotherapy, respectively. The results of Tables 4 and 5 are summarized in Table 6. In clinical response, 89% of the cases with Grade 4 mucositis corresponded to the cases of PR or CR, while only 33% of the cases with Grade 1 mucositis showed PR or CR (Table 6). Statistically, the severity of oral mucositis correlated with the degree of clinical tumor response (P < 0.05) (Table 4). Likewise, all the tumor cells observed in the specimen appeared to be histopathologically dead (Grades III and IV) after preoperative therapy in 55% of the cases with Grade 4 mucositis, 31% with Grade 3 mucositis, 24% with Grade 2 mucositis and 0% with Grade 1 mucositis (Table 6). The grade of histopathological tumor response also significantly correlated to the severity of oral mucositis (P < 0.05) (Table 5). In contrast, only four cases (7%) of severe mucositis had less tumor reduction and seven cases (13%) with mild mucositis showed extensive tumor death. These data suggest that the severer the
Table 4. Relationship between oral mucositis and clinical tumor response* Severity of oral mucositis Clinical response CR PR NC PD Total *
Grade 1
Grade 2
Grade 3
Grade 4
Total
0 1 2 0
2 16 10 1
2 9 2 0
2 6 1 0
6 32 15 1
3
29
13
9
54
x2 test: P < 0.05.
Table 5. Relationship between oral mucositis and histopathological tumor response* Severity of oral mucositis Histopathological tumor response Grade Grade Grade Grade Grade
I IIa IIb III IV
Total *
Grade 1
Grade 2
Grade 3
Grade 4
Total
0 1 2 0 0
0 10 12 1 6
0 3 6 2 2
0 1 3 3 2
0 15 23 6 10
3
29
13
9
54
2
x test: P < 0.05.
Table 6. Severity of oral mucositis in good tumor responders to neoadjuvant radiochemotherapy Good tumor responders Oral mucositis grade
CR + PR*
Grade Grade Grade Grade
1 18 11 8
1 2 3 4
(n = 3) (n = 29) (n = 13) (n = 9)
(33%) (62%) (85%) (89%)
Grades III + IV** 0 (0%) 7 (24%) 4 (31%) 5 (55%)
Data in parentheses in columns 2 and 3 express percentage in each grade of oral mucositis. * Clinical tumor response. ** Histopathological tumor response.
development of oral mucositis, the more the tumor cells were damaged by the concurrent radiochemotherapy. Discussion
In the present retrospective study, we found that the severity of oral mucositis correlated with clinical and histopathological tumor response to preoperative radiochemotherapy in oral squamous cell carcinoma. Both radiotherapy and chemotherapy induce oral mucositis as an unpleasant, adverse effect. Radiotherapy for oral cancer directly affects normal oral mucosa to give rise to oral mucositis. Combined with chemotherapy, where some anti-cancer drugs work as radiation sensitizers, radiation should more severely impair oral mucosa. However, some patients suffered from severe oral mucositis, while oral mucositis of others was mild, suggesting that the sensitivity of oral mucosa to radiochemotherapy is determined by such intrinsic factors as genes. Some of the genetic factors involved in the radiosensitivity of normal oral mucosa are likely to be shared with oral squamous cell carcinoma, as the present study showed that the response of oral cancer to radiochemotherapy correlated with the susceptibility of normal oral mucosa to the therapy in many cases. In addition, the radiosensitivity of normal skin fibroblasts is reported to correlate with that of squamous carcinoma cells in the same individual4. Because oral mucositis worsens quality of life, various methods of managing, treating and preventing oral mucositis have been reported5. Recently, an oral rinse, including such growth factors as granulocyte and granulocyte–macrophage colony-stimulating factors3 and keratinocyte growth factor11, which promote the restoration of damaged epithelial cells, has been applied to oral mucositis. However, in oral cancer, the topical application of growth factor may in fact stimulate the proliferation of tumor cells. We usually control the symptoms of oral mucositis with topical use of steroid and oral rinse containing lidocaine and proteases. Although steroid may increase the risk of infection in oral mucosa, it can also decrease the inflammatory reactions in the mucosa. Steroid is also reported to inhibit the production of the invasion-related proteases in oral cancer2. As oral mucositis is thought to be induced by inflammatory cytokines such as interleukin-1 and tumor necrosis factor a, which are released from mucosal tissues stressed by radiation and anti-cancer drugs10, anti-cytokine therapy
Oral mucositis and tumor response is expected to be an efficient method for reducing oral mucositis. Because the sample size was small in this study, we could not relate oral mucositis grade to tumor site and stage. Likewise, the severity of oral mucositis could not be compared with recurrence and survival rate. Moreover, it is uncertain whether the severity of mucositis is more related to the radiotherapy than the chemotherapy. Further study with a larger sample size is required to solve these problems. In conclusion, severe oral mucositis may promise a good response of oral squamous cell carcinoma to preoperative radiochemotherapy. References 1. ANONYMOUS. Handbook for Reporting Results of Cancer Treatment. Vol 48: WHO Offset Publication 1979: 15–22. 2. Beppu M, Ikebe T, Shirasuna K. The inhibitory effects of immunosuppressive factors, dexamethasone and interleukin4, on NF-kB-mediated protease production by oral cancer. Biochim Biophys Acta 2002: 1586: 11–22.
3. Chi KH, Chen CH, Chan WK, Chow KC, Chen SY, Yen SH, Chao JY. Effect of granulocyte-macrophage colony-stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil and leucovorin chemotherapy. J Clin Oncol 1995: 13: 2620–2628. 4. Haikonen J, Rantanen V, Pekkola K, Kulmala J, Grenman R. Does skin fibroblast radiosensitivity predict squamous cancer cell radiosensitivity of the same individual? Int J Cancer 2003: 103: 784–788. 5. Mead GM. Management of oral mucositis associated with cancer chemotherapy. Lancet 2002: 359: 815–816. 6. Ozeki S, Okamoto M, Tashiro H, Jingu K. The effects of combined radiation and bleomycin therapy on the cervical lymph nodes metastasized from oral cancer. J Jpn Soc Cancer Ther 1986: 21: 664–670. 7. Parulekar W, Mackenzie R, Bjarnason G, Jordan RCK. Scoring oral mucositis. Oral Oncol 1998: 34: 63–71. 8. Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinomas. Jpn J Oncol 1971: 1: 19–35.
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9. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998: 34: 39–43. 10. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004: 4: 277–284. 11. Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre F, Sung EC, Blazar BR, Elhardt D, Chen M-G, Emmanouilides C. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004: 351: 2590–2598. Address: Tetsuro Ikebe Department of Oral and Maxillofacial Surgery Sensory and Motor Organ Sciences Faculty of Medical and Pharmaceutical Sciences Kumamoto University 1-1-1 Honjyo Kumamoto 860-8556 Japan Fax: +81 96 373 5286 E-mail: [email protected]