Abstract
Background/Aim: Oral mucositis (OM) is one of the frequent adverse events experienced by patients receiving chemotherapy. Most diagnoses of OM are based on complaints from patients. The aim of this study was to develop a tool to diagnose OM accurately. Materials and Methods: A central review system (CRS) was created to allow judgment when the patient background is completely unknown. The primary endpoint was the rate of grade 2 or higher OM, and the secondary endpoint was the difference in grade between each institution's clinician judgement and that of the CRS. Results: In total, 53 patients were registered from four institutions. CRS successfully detected grade 2 or higher OM in 16 (30.2%) of the 53 patients. The detection rate of all grades of OM was 41.5% (22 of 53 patients) by each institution's clinician judgement and 84.9% (45 of 53 patients) by CRS judgement (p<0.0001). Conclusion: OM during chemotherapy may be underestimated.
Esophageal cancer is a malignant disease carrying a poor prognosis in spite of R0 resection (1). In a previous report, the 5-year survival rates of patients with stage I, II, III, and IV esophageal cancer were 90%, 45%, 20%, and 10%, respectively (2). Recent advances in surgical techniques have reduced complications for advanced esophageal cancer, but the 5-year survival rate is only 20-36% (3). Even patients with submucosal infiltration have a high potential for lymph node metastases, and the rate of lymph node metastasis is reported to range from 16-62% (4). The survival of esophageal cancer patients is strongly associated with the extent of lymph node metastasis (5-7).
In patients with operable and node-positive advanced esophageal cancer, there is evidence supporting the use of neoadjuvant chemotherapy or chemoradiation (8, 9). Also, metastatic esophageal cancer has been treated with chemotherapy (10), which can significantly improve the survival rate of patients, but causes adverse effects (11, 12). The standard neoadjuvant chemotherapy is 5-fluorouracil (5-FU)/ cisplatin (FP) (13). The combination of docetaxel/cisplatin/ 5-FU (DCF) has become widespread, because of the expectation of higher effectiveness (14). To overcome adverse events including hematological toxicities, we reported a biweekly-DCF regimen which can reduce hematological toxicity (15, 16).
Oral mucositis (OM) results in increased pain, difficulty in swallowing, nutritional compromise, and infection. All anticancer agents used in DCF are reported to cause mucosal damage, with an incidence rate of few to as much as 70% (17, 18). However, several countermeasures to prevent OM have been reported (19-21), but their effects might not be sufficient to combat multi-drug anticancer therapies.
One report indicated that administration of oral glutamine (Gln) reduced OM after cancer chemotherapy (22). We previously conducted a randomized phase II trial to verify the effects of Gln plus elemental diet (ED, (Elental®; EA Pharma Co., Ltd.). Only the Gln plus ED group showed a preventive effect. The ED contains amino acids such as histidine, which has an anti-inflammatory effect (23). The higher level of plasma diamine oxidase activity was achieved in Gln plus ED group (24).
In our next study, the ‘EPOC feasibility study’ (Feasibility study of the effect of Elemental diet with docetaxel, cisplatin and fluorouracil (DCF) in Preoperative Oesophagus Cancer patients: A multi-center prospective feasibility study), which has already been reported, we investigated compliance to ED that could feasibly be administered in combination with a DCF regimen. We found that 70% of patients completed the orally administered regimen of ED (160 g/day) (25).
Importantly, the exact objective incidence of OM was not clarified because its incidence was based on complaints of patients or assessment by general physicians or medical staff who are not specialists in the oral environment, and thus the incidence of OM might have been underestimated. A thorough examination of the intraoral condition by use of instruments designed for the oral cavity can only be conducted by oral and maxillofacial surgeons, dentists, and their teams.
Considering the above situation, a central review system (CRS) was developed for judging the oral environment. To determine the feasibility and objectivity of this system, a multi-center, prospective, observational cohort study was conducted on the incidence of OM in esophageal cancer patients treated with practical chemotherapy using the CRS.
Materials and Methods
Establishment of a CRS for practical chemotherapy. Initially, we developed the CRS in line with a multi-center, prospective, observational cohort study investigating practical chemotherapy for esophageal cancer. Patients with esophageal cancer undergoing chemotherapy with FP or triplet regimen were enrolled from 4 institutions: Gifu University Hospital, Keio University Hospital, Kumamoto University Hospital, and Chiba University Hospital. Dentists and oral and maxillofacial surgeons at each institution used instruments specific for the oral cavity and a specialized intraoral imaging camera to take six photographs of the posterior surface of the upper and lower lip, right and left buccal mucosa, and right and left lingual surfaces of each patient (Figure 1) and stored them as 4-megabyte electronic files in the CRS data server before the start of chemotherapy and at every cycle of chemotherapy without grading OM.
In addition, each institution's clinicians assessed and recorded the incidence and grade of OM at bedside without specific instruments for the oral cavity. Treatment of OM, if needed, was at the discretion of the clinicians of each institution as daily routine medical management of OM.
Separately, a dental specialist who was well experienced in dental oncology (TU), not affiliated with any of the registered institutions, and unaware of the patients' backgrounds assessed the incidence and grading of OM using the CRS after the end of all registered patient's chemotherapy.
OM was graded by using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (2003) as follows: Grade 1, erythema of the mucosa; Grade 2, patchy ulcerations or pseudo-membranes; Grade 3, confluent ulcerations or pseudomembranes, bleeding with minor trauma; Grade 4, tissue necrosis, significant spontaneous bleeding, life-threatening consequences; and Grade 5, death. The judgment grade was recorded for all patients, and any difference between the CRS judgement and that made at the bedside by each institution's clinicians was investigated.
Endpoints. The primary endpoint of this study was validity of the CRS judgment. In other words, verification of the rate of grade 2 or higher OM occurred in daily clinical practice as judged by the CRS. The secondary endpoints were the difference between the judgment by each institution's clinicians at the bedside and the CRS judgement and all adverse events other than OM that resulted from daily esophageal cancer chemotherapy.
Eligibility criteria. Patients who were >18 years of age at the time of registration and who had histologically or cytologically confirmed esophageal squamous cell carcinoma or adenocarcinoma were included. The other inclusion criteria were as follows: an Eastern Cooperative Oncology Group performance status of 0-2; a life expectancy of >12 weeks; adequate liver, bone marrow, renal, and cardiovascular functions (serum bilirubin ≤1.5 mg/dl; neutrophil count ≥1500/mm3; serum aspartate aminotransferase and alanine aminotransferase levels ≤ twice the upper limit of normal range; platelet count ≥10×104/mm3; hemoglobin ≥8.0 g/dl; and creatinine ≤1.2 mg/dl).
The major exclusion criteria were serious concomitant illness, symptomatic infectious disease, severe allergy, peripheral neuropathy, or uncontrolled diabetes mellitus.
Ethical considerations. This trial was conducted in accordance with the World Medical Association Declaration of Helsinki and was registered with the University Hospital Medical Information Network Clinical Trials Registry (Registration number: UMIN000014573). The study protocol was approved by the independent ethics committees of each of the four participating institutions, and written informed consent was obtained from all of the patients.
Statistical analysis. The differences in the judgement of OM between each institution's clinicians and the CRS was analyzed by Wilcoxon rank sum test and Fisher's exact test. p-Values of <0.05 were considered to indicate statistical significance. All statistical analyses were performed using the SAS software program (ver. 9.4; SAS Institute Inc., Cary, NC, USA).
Results
Establishment of a CRS for practical chemotherapy. Chemotherapy for esophageal cancer was performed in 53 patients between January 2013 and March 2015. Patient characteristics are shown in Table I. All 53 patients were enrolled, and all were targeted as subjects for the analysis of the primary endpoint. The median age was 67 years (range=50-81 years). Performance status was 0 in 16 patients and 1 in 27 patients. Tissue types included squamous cell carcinoma in 52 (98.1%) patients and adenocarcinoma in 1 (1.9%) patient. Chemotherapy regimens performed were a DCF regimen in 36 (67.9%), DGS (docetaxel, nedaplatin, and S-1) regimen (26) in 7 (13.2%), and the FP regimen in 10 patients (18.9%).
Schema of the intraoral photographs for the central review system. Oral and maxillofacial surgeons used a specialized intraoral imaging camera to take six photographs of the posterior surface of the upper and lower lip, right and left buccal mucosa, and right and left lingual surface.
Patient characteristics.
Central review of oral photographs using the CRS was achieved for all patients, and the CRS judge could assess the incidence and grading with objectivity. Accordingly, OM of all grades occurred in 45 patients (84.9%, 95% confidence interval (CI)=72.4-93.3%). OM of grade 2 or higher was found in 16 patients (30.2%, 95%CI=18.3-44.3%).
The all grades of OM judged by each institution's clinicians at the bedside was 41.5% (22 of 53 patients; 95%CI=28.5-55.9%). Judgment of all grades of OM by each institution's clinician was significantly lower than that made with the CRS (p<0.0001) (Table II).
All adverse events. Among hematological adverse events, grade 3 or higher leucopenia occurred in 18 (34.0%) and grade 3 or higher neutropenia occurred in 19 (35.8%) patients. Among the non-hematological adverse events, anorexia of grade 2 or higher occuured in 10 patients (18.9%), and diarrhea of grade 2 or higher occurred in 2 patients (3.8%). Anorexia of grade 3 was recognized in 3 patients (5.7%) (Table III).
Difference of judgement between each institution's clinicians and CRS.
Adverse events (n=53).
Discussion
This is the first study, to our knowledge, of the development of a CRS for judgment of OM by a dental specialist well experienced in dental oncology who could judge OM in an unbiased manner, without knowledge of the patient's background. Moreover, dentists at each participating institution used special equipment for intraoral photography which were stored in a central server at high resolution. The incidence of OM (grade ≥1) during chemotherapy has been reported to be higher in breast cancer (76.5%), followed by head and neck cancer (67.7%), colorectal cancer (63%), and esophageal cancer (57.8%). The incidence of OM was higher in DCF (85.7%), followed by 5-FU/ leucovorin/irinotecan (80%), and 5-FU/cyclophosphamide/adriamycin (78.8%). The incidence of OM of grade ≥2 among patients receiving DCF was approximately 40% (27).
In this prospective cohort study, intraoral assessment via an objective central review system by an oral and maxillofacial surgery specialist as CRS judge could be performed in all cases and this study suggested that the rate of OM occurrence during esophageal cancer chemotherapy with triplet regimen including 5-FU in actual clinical settings was not at all low: in patients not receiving ED, all grades of OM occurred in 22 of 23 patients (95.7%, 95%CI=78.1-99.9%) and grade 3 or higher occurred in 3 of 23 patients (13.0%, 95%CI=2.8-33.6%), whereas in other reports of triplet regimen chemotherapy including 5-FU, all grades of OM occurred in 10%-64% and grade 3 or higher OM occurred in 0.0-6.7% of patients (14, 16, 28).
Therapeutic drugs and the presence or absence of ED.
Incidence rates per grade of oral mucositis and incidence rates of oral mucositis with and without ED in the observational study using CRS.
Interestingly, the incidence rate of all grades of OM reported from each institution's bedside clinicians, who were not experts in the oral environment, was 41.5% in this cohort study, whereas the rate determined by the CRS judge was 84.9%. We think that methods of intraoral observation using instruments that are specific to oral surgery specialists improve accuracy but they may not be easily used by general clinicians.
It can be seen that the incidence of OM is higher compared to other non-hematologic toxicities during chemotherapy (Table III). Similar to this study, cardiovascular toxicity, dermatological toxicity, nausea, vomiting, diarrhea, constipation, fatigue, infection, thrombosis, and OM have been reported to account for the majority of non-hematologic toxicities of anticancer drugs. Specific preventive methods and recommendations for handling chemotherapy adverse events other than OM have been made (29). OM has a strong impact on patient's quality of life: the burning sensation patients experience may limit basic functions such as speech, eating, or swallowing saliva.
Cytostatic agents such as 5-FU and taxanes and the frequency of administration (prolonged or repeated low-dose administrations) are strongly related to OM (30). According to the MASCC/ISOO Clinical Practice Guidelines, palifermin is the only agent that has been approved as a drug by the US Food and Drug Administration and the European Medicines Agency for OM (31). In the MASCC/ISOO and ESMO guidelines, oral care protocols are recommended (31, 32). A review article has reported that oral hygiene protocols, amifostine, benzydamine, calcium phosphate, cryotherapy, and iseganan yield only limited benefits (33). Although oral care and guidance to patients from dentists concerning oral care were performed in 51 of the 53 patients (96.2%) in the present study, OM still occurred. Because palifermin is not covered by insurance in Japan, no effective prophylaxis for chemotherapy-induced OM currently exists.
Recent studies have shown that amino acids have a mucosal protective effect and anti-inflammatory effects (34, 35). Even in this actual clinical setting of esophageal cancer chemotherapy, OM tended to be suppressed by the combined use of ED. In this study, 8 patients (15.1%) were treated in combination with administration of ED and 45 patients (84.9%) were treated without ED. There were no significant differences in chemotherapy regimens between the groups with or without ED administration (Table IV). Using the CRS, we found that the incidence rate of OM of grade 2 or higher tended to be higher in the group without ED (1 of 8 patients (12.5%) in the group with ED, 95%CI=0.3-52.7%, and 15 of 45 patients (33.3%) in the group without ED, 95%CI=20.0-49.0%; p=0.4098, Fisher's exact test) (Table V).
According to Van der Velden et al., neutropenic patients who receive cytotoxic therapy experience mucosal barrier injury or OM. Mucosal barrier injury creates a port-de-entrée for resident microorganisms to cause bloodstream infections and contributes directly to the occurrence of fever by disrupting highly regulated host-microbe interactions, which, even in the absence of an infection, can result in inflammatory reactions. Hence, the concept of ‘febrile neutropenia’ alone may no longer suffice, and a new concept of ‘febrile mucositis’ should be recognized as these two concepts are at least complementary. Importantly, this phenomenon is occurring not only in the oral cavity but also in the entire gut (36). Our previous report (24) also showed that chemotherapy reduced the integrity of the intestinal mucosa and a combination of ED and Gln significantly maintained integrity during chemotherapy, indicating that there might be a connection with the environment of the oral cavity. The low value of plasma diamine oxidase activity in patients with OM in that report may prove this ‘febrile mucositis’ concept. In other words, the possibility that OM is a marker of the failure of the mucosal defense function of the intestinal tract has been suggested. For this reason, we think that it is necessary to recognize the importance of correctly evaluating chemotherapy-induced OM. In fact, a discrepancy has been reported between the complaint of the patient and the judgment of the physician (37).
This study has two limitations. First, as esophageal cancer itself is a rare cancer, the number of enrolled patients is small. Second, a single dental specialist was used as a CRS judge.
Conclusion
We found that the use of a CRS is feasible and that patients undergoing chemotherapy for esophageal cancer developed OM at a consistent frequency. Collaboration with oral surgery specialists is meaningful in research to accurately investigate the incidence of OM, and clinical cooperation is clearly possible. The incidence of chemotherapy-induced OM may be underestimated.
Acknowledgements
This study was partly supported by grants from the clinical trial program for cancer 2016 in the Japan Society of Clinical Oncology and was partly funded by EA Pharma Co., Ltd., Tokyo, Japan. The Authors would like to thank Rise Japan for providing editorial assistance and Meditrix K.K. for analyzing the data.
Footnotes
Authors' Contributions
KY and YK conceived the study concept and planned the design as principal investigators. YT interpreted the results and drafted the manuscript. KY revised the manuscript draft by adding intellectual insights and providing critical advice. TU, NY, YA, HT, HB, HM, YK, and KY obtained the data and provided their critical comments to improve the manuscript, and all Authors gave final approval of the final version of the manuscript.
Conflicts of Interest
Dr. Yoshida reports grants, personal fees, and non-financial support from EA Pharma Co., Ltd., Sanofi, Yakult Honsha Co., Ltd., Chugai Pharma Co., Ltd., Taiho Pharma Co., Ltd., Takeda Pharma Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Ono Pharma Co., Ltd., Merck Serono Co., Ltd., and Novartis Pharma K.K., and grants from Kyowa Hakko Kirin Co., Ltd. outside the submitted work. Dr. Kitagawa reports grants and honoraria from Yakult Honsha Co., Ltd., Taiho Pharma Co., Ltd., grants from Kyowa Hakko Kirin Co., Ltd., and honoraria from Sanofi K.K., Pfizer Co., Ltd., Nippon Kayaku Co., Ltd., and Bristol-Myers Squibb outside the submitted work. Dr. Matsubara reports grants from EA Pharma Co., Ltd., Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., and Taiho Pharma Co., Ltd. outside the submitted work. Dr. Baba reports grants from EA Pharma Co., Ltd. outside the submitted work.
- Received June 26, 2019.
- Revision received July 2, 2019.
- Accepted July 3, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
