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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 932-937

Acute toxicities of adjuvant treatment in patients of oral squamous cell carcinoma with and without submucous fibrosis: A retrospective audit


1 Department of Head and Neck Surgery, TATA Memorial Hospital, Parel, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, TATA Memorial Hospital, Parel, Mumbai, Maharashtra, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Swagnik Chakrabarti
Department of Head and Neck Surgery, TATA Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.174187

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 > Abstract 


Objective: To assess the severity of acute toxicities of postoperative adjuvant therapy on oral squamous cell carcinoma (OSCC) patients with and without submucous fibrosis (SMF).
Materials and Methods: The study population comprised treatment naïve OSCC patients who underwent curative intent surgical resection from June 2010 to April 2011 followed by adjuvant treatment. Patients whose treatment details including toxicity profile were available were included in the study. One-hundred nine patients met the inclusion criteria of whom 36 had associated SMF and 73 no SMF. Overall, 35 patients received chemotherapy (CT) with radiotherapy (RT) and the rest only RT. Forty-two patients had centralized and 67 lateralized lesions. All patients with centralized lesions and 3 with lateralized lesion received radiation to bilateral face and neck. All others received ipsilateral radiation. The severity of mucositis, xerostomia, and skin toxicity (as per radiation therapy oncology group scale of acute toxicity) was compared between the SMF and non-SMF groups and patients with centralized and lateralized lesions.
Results: CT in addition to RT did not add significant to the assessed toxicities. Severe mucositis as well as treatment breaks were more in SMF group as compared to non-SMF group (P = 0.001 and <0.001 respectively). Severe mucositis and xerostomia were more in centralized than in lateralized lesions (P = 0.002 and 0.00 respectively). In subgroups of lateralized as well as centralized lesions, severe mucositis was more common in SMF patients than those without SMF (P = 0.01 and 0.02 respectively).
Conclusion: OSCC patients with SMF have worse toxicity with adjuvant therapy and require good supportive care.

Keywords: Centralized lesions, lateralized lesions, oral squamous cell carcinoma, submucous fibrosis


How to cite this article:
Chakrabarti S, Mishra A, Agarwal JP, Garg A, Nair D, Chaturvedi P. Acute toxicities of adjuvant treatment in patients of oral squamous cell carcinoma with and without submucous fibrosis: A retrospective audit. J Can Res Ther 2016;12:932-7

How to cite this URL:
Chakrabarti S, Mishra A, Agarwal JP, Garg A, Nair D, Chaturvedi P. Acute toxicities of adjuvant treatment in patients of oral squamous cell carcinoma with and without submucous fibrosis: A retrospective audit. J Can Res Ther [serial online] 2016 [cited 2019 Dec 10];12:932-7. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/932/174187




 > Introduction Top


Oral submucous fibrosis (SMF) is a premalignant lesion related to areca nut chewing and is widely prevalent in South-East Asia.[1],[2] The annual malignant transformation rate is about 0.5%[3] with an overall malignant transformation rate being 3–6%.[2] In a previous publication from our center,[4] we found that oral squamous carcinoma (OSCC) arising in a background of SMF is a distinct entity with less aggressive clinicopathological factors and a better prognosis. In this study, we compared the incidence of acute toxicities of adjuvant treatment in OSCC patients with and without SMF.


 > Materials and Methods Top


Even after adequate surgical treatment for OSCC, many patients fail to complete adjuvant radiotherapy (RT) with or without chemotherapy (CT) or have treatment breaks owing to treatment-related toxicities. Many factors contribute to this and essentially include the severity of treatment-related toxicities, nutritional status, and supportive care. The severity of toxicity of adjuvant treatment varies between patients and cannot be adequately predicted before the starting of treatment. Associated SMF may be a contributory factor owing to the already compromised local environment which is not able to tolerate the insults of RT and CT. We assumed that OSCC patients with SMF may be candidates for poor compliance who would need better nutritional and supportive care in the peritreatment period. Based on this hypothesis, we conducted a retrospective observational study to assess the severity of acute toxicities of RT alone or with (CT + RT) in OSCC patients with SMF and compared them with OSCC patients who did not have SMF. To our knowledge, there has been no study reported in literature from our country or abroad addressing this issue.

A meticulous search of our database was done to identify treatment naïve patients of OSCC, who underwent curative intent surgical resection in our institute in a period of June 2010–April 2011 followed by adjuvant treatment (RT or CT + RT) in our institute or elsewhere. Patients whose treatment details including toxicity profile at 3 months of completion of treatment were available were included in the study. The toxicity profiles assessed were acute mucositis, skin toxicity, xerostomia, weight loss, and trismus.

Patients undergoing surgery elsewhere or with recurrent or second primary tumors were excluded.

Of the 371 OSCC patients who underwent surgery in the previously mentioned period, 109 met the inclusion criteria. These patients were divided into two groups such as SMF group and non-SMF group. The diagnosis of SMF was based on the following clinical criteria: intolerance to hot and spicy foods, pale looking oral mucosa, palpable mucosal fibrotic bands, and chronic progressive trismus.[5],[6] There were 36 patients in the SMF group and 73 patients in the non-SMF group [Table 1].
Table 1: Patient and site distribution

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Based on the principles of RT, patients with tumors that involve the midline structures receive radiation to bilateral (B/L) face and neck while those with lateralized tumors mostly receive radiation to the ipsilateral side. To differentiate patients who were planned to receive B/L versus unilateral radiation fields, tumors of the oral tongue, middle 1/3rd mandible, hard palate, and midline lip were classified as “centralized” whereas tumors arising at other subsites of the oral cavity were classified as “lateralized lesions.” There were 67 patients with lateralized lesions and 42 with centralized lesions [Table 1].

Patients with centralized and lateralized lesions were found to be symmetrically distributed between SMF and non-SMF groups [Table 2].
Table 2: Site distribution between submucous fibrosis and nonsubmucous fibrosis groups (n=109)

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In the present study, all patients with centralized lesions received radiation to B/L face and neck. All patients with lateralized lesions received radiation to ipsilateral face and neck excepting three who received radiation to B/L face and neck (all 3 were in the OSCC without SMF group). This was due to tumor metastasis to level IA or contralateral neck nodes in all these three patients.

None of the patients had positive or close margins of resection. CT + RT were indicated only in patients who had nodal metastasis with extracapsular extension. About 2/3rd of all patients received postoperative RT while the rest 1/3rd received CT + RT. All patients received RT using telecobalt machine with conventional technique. Patients indicated for CT + RT were planned for weekly dose of 30 mg/m 2 of cisplatin for a maximum of 6 weeks along with RT. Interestingly, of the patients who received CT + RT, 80% were in non-SMF group and 20% in SMF group [Table 3].
Table 3: Type of adjuvant treatment in submucous fibrosis and nonsubmucous fibrosis groups

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All patients on first follow-up (3 months post completion of treatment) were evaluated for the severity of the following toxic reactions-acute mucositis, skin toxicity, xerostomia, weight loss, and trismus. The severity of mucositis, skin toxicity, and xerostomia was evaluated using the radiation therapy oncology group scale for acute toxicities [Table 4].[7] Weight loss was calculated by substracting the posttreatment weight at 3 months of follow-up from the pretreatment weight recorded before surgery. Mouth opening ≤2 cm was recorded as trismus.
Table 4: The radiation therapy oncology group scale of acute toxicities[7]

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Patients up to Grade 2 toxicities were classified to having mild toxicities while those with Grade 3 and 4 toxicities were classified to have severe toxicities. The data on mucositis, skin toxicity, and xerostomia were available for all 109 patients. Data on weight loss were available for 107 patients and data on trismus were available for only 41 patients.

The toxicity profiles were compared between patients in SMF (n = 36) and non-SMF (n = 73) groups and patients with centralized (n = 42) and lateralized (n = 67) lesions. In patients with centralized lesions, the toxicity profile between SMF and non-SMF groups was compared. Similar comparisons were made in patients with lateralized lesions. Comparisons of toxicity profile were also made between lateralized and centralized lesions in patients in SMF group as well as those in non-SMF groups.

Statistical analysis

Data were analyzed using IBM SPSS Statistics for Windows, version 20.0 (Version 20.0. Armonk, NY: IBM Corp.). Categorical variables were compared using Chi-square test and Fisher's exact test. Continuous variables analyzed using t-test for normally distributed variables, and median test was used for nonnormal continuous variables.


 > Results Top


The male:female ratio in SMF and non-SMF groups was 8:1 and 3.3:1, respectively. The mean age in SMF group and non-SMF group was 43.47 years (range: 25–69 years) and 49.75 years (range: 30–78 years), respectively [Table 5].
Table 5: Age and gender distribution

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The mean dose of radiation to patients in OSCC with SMF and OSCC without SMF were 59.61 Gy (range: 56–60 Gy) and 59.22 Gy (range: 50–70 Gy), respectively. Four of 7 patients (57.14%) in SMF group and 22 of 28 patients (78.57%) in non-SMF group completed 6 cycles of cycles of CT.

CT + RT as compared to RT alone did not have significant increase in toxicity in any of the parameters assessed [Table 6].
Table 6: Acute toxicities-chemotherapy + radiotherapy versus radiotherapy alone

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The toxicities of adjuvant treatment in OSCC patients with and without SMF were compared [Table 7]. Severe mucositis and skin toxicity were significantly more in SMF group as compared to non-SMF group (P = 0.001and 0.015 respectively). Treatment breaks were significantly more common in SMF group as compared to non-SMF group (P < 0.001).
Table 7: Acute toxicities-submucous fibrosis versus nonsubmucous fibrosis groups

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The toxicities of adjuvant treatment were compared between lateralized and centralized lesions [Table 8]. Severe mucositis and xerostomia were significantly more in patients with centralized lesions as compared to those with lateralized lesions (0.02 and 0.00, respectively).
Table 8: Acute toxicities-centralized versus lateralized lesions

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In patients having lateralized lesions (n = 67), nearly 1/3rd (31.34%) had associated SMF, and the rest 2/3rd (68.66%) did not have SMF. The toxicity profile of SMF and non-SMF patients having lateralized lesions were compared [Table 9]. Severe mucositis was significantly more common in SMF group as compared to non-SMF group (P = 0.016).
Table 9: Acute toxicities in lateralized lesions-comparison between submucous fibrosis and nonsubmucous fibrosis groups

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In patients with centralized lesions (n = 42), 35.71% had associated SMF and the rest 64.29% did not have SMF. The toxicity profile of SMF and non-SMF patients having centralized lesions were compared [Table 10]. Severe mucositis was significantly more in the SMF as compared to the non-SMF group (P = 0.04)
Table 10: Acute toxicities in centralized lesions- comparison between submucous fibrosis and nonsubmucous fibrosis groups

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In patients in SMF group (n = 36), 41.66% had centralized lesions and 58.33% had lateralized lesions. Xerostomia was significantly more in patients with centralized lesion (P = 0.00). Severe mucositis had a increased incidence in centralized lesions though the difference did not achieve statistical significance (P = 0.08) [Table 11].
Table 11: Acute toxicities in submucous fibrosis group-comparison between centralized and lateralized lesions

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In patients in non-SMF group (n = 73), 36.98% had centralized lesions while 63.01% had lateralized lesions. Severe mucositis and xerostomia were more common in centralized lesions although only the incidence of severe mucositis attained statistical significance (P = 0.016) [Table 12].
Table 12: Acute toxicities in nonsubmucous fibrosis group-comparison between centralized and lateralized lesions

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 > Discussion Top


Although the mean dose of radiation was similar in patients with and without SMF, the range differed. The maximum dose of radiation received in the SMF and the non-SMF groups were 60 Gy and 70 Gy, respectively. Six patients in non-SMF group tolerated radiation dose of more than 60 Gy with 2 of them receiving 70 Gy of radiation. None of the patients in the SMF group could receive more than 60 Gy of radiation. Similarly, four patients (57.14%) in SMF group completed six cycles of CT as compared to 22 patients (78.57%) in non-SMF group. This reflects that overall toxicity of adjuvant therapy was more in the SMF group as compared to the non-SMF group.

Of the 35 patients receiving CT + RT, 80% were in SMF group and only 20% in non-SMF group. As none of the patients had positive margin of resection, the only indication for adjuvant CT + RT was extracapsular nodal extension. Thus, more patients in non-SMF group had extracapsular nodal extension, and this is a reflection of the more aggressive nature of the disease in patients in non-SMF group. This is in conjunction to a previous published study from our institute which has highlighted the less aggressive clinical and pathological parameters in OSCC patients with SMF.[4]

Interestingly, in our study, although patients receiving CT + RT had more incidences of severe toxicities as compared to those receiving RT alone, the difference did not receive statistical significance in any of the parameters assessed. This is in sharp contradiction to most studies [8],[9] and may be due to the small sample size in the study receiving adjuvant CT + RT (32.1%) as compared to RT alone (67.8%).

Severe mucositis was significantly more common in the SMF group as compared to the non-SMF group. Normally, oral mucosal epithelium has a rapid renewal over a 7–14 days cycle. This helps in clearing micro-organisms and maintains a chemical barrier to combat insults. However, due to fibrosis and hyalinization of subepithelial tissue, the vascular supply to the mucosa is impaired which leaves the mucosa less resistant to toxic agents such as RT.[1],[10] The high number of treatment breaks in SMF group (55.5%) as compared to non-SMF group (9.5%) further signifies the severity of mucositis in the former group of patients.

There was also a significant increase in severe skin reactions in SMF group. This difference cannot be explained and may be a result of small number of patients in each group (6 in SMF and 2 in non-SMF group). Drawing definite conclusion from this finding is not possible. Although patients in SMF group had more mean weight loss, the difference was not significant mainly due to the good supportive care and prolonged tube feeding in this group of patients.

All patients with centralized lesions received radiation to B/L face and neck and all but three patients with lateralized lesions received radiation to ipsilateral face and neck. The three patients with lateralized lesions who received B/L radiation had nodal metastasis to level IA or contralateral neck nodes. All these three patients were in non-SMF group again signifying the aggressive nature of the disease in this group of patients. The radiation fields to patients with centralized lesions covered B/L parotid glands. As the parotids are superficially located as compared to the oral cavity, ionizing radiation has to pass through the parotids to effectively reach the site of action.[11] Although the acinar cells of the parotids have a slow turnover rate, they are not as radioresistant as they are supposed to be.[12] The radiation dose required for severe damage of the gland tissue is >52 Gy.[13] The major reduction in salivary flow rates occurs from the onset of radiation to 3 months postcompletion.[14] As all patients of centralized lesions received radiation to B/L parotids as compared to most patients of lateralized lesion who received radiation to ipsilateral parotids, severe xerostomia was significantly more common to patients with centralized lesions (P = 0.00). It, however, would have been interesting to see whether this difference persisted even after 3 months of completion of radiation when there is progressive recovery of the parotid acinar cells.

Subgroup analysis showed that mucositis and xerostomia were worse for centralized lesions both in SMF group and non-SMF groups. In SMF group, severe xerostomia was present in 60% of the patients with centralized lesions as compared to 4.8% with lateralized lesions (P = 0.00). Similarly, in non-SMF group, severe xerostomia was more common in patients with centralized lesions (33.3%) as compared to those with lateralized lesions (13%) (P = 0.06). The more pronounced xerostomia in SMF group may be due to the pathological changes in the submucosal layers that affect the parotids also resulting in increased insults from adjuvant therapy. However, the numbers of patients were less to draw definitive conclusions.

Our study had certain limitations. First, it was a cross-sectional study which assessed the toxicities of adjuvant treatment at one point of time (around 3 months postcompletion of treatment). A longitudinal follow-up would have yielded better assessment of the toxicities. Second, the data on trismus were present only in the posttreatment period. Pretreatment evaluation of trismus was not documented. As trismus is common in pretreatment oral cancer patients either due to pain, masticator muscles involvement or SMF, conclusions cannot be drawn on the role of adjuvant treatment on posttreatment trismus. Moreover, data on trismus were available only on 41 patients, which are too less to draw conclusions. Finally, the weight loss was also calculated based on the pretreatment weights. As major resections of the oral cavity impair oral preparatory and oral phases of swallowing significantly, surgery remains a major contributing factor to weight loss and acts as a confounding factor in assessment of weight loss as a result of adjuvant treatment.


 > Conclusion Top


OSCC patients with SMF are more prone to toxicities of adjuvant therapy, especially mucositis. OSCC patients with SMF with centralized lesions also have increased incidence of severe xerostomia. They are prone to treatment breaks and incomplete treatment as a result of toxicities. Thus, these patients need good nutritional and supportive care in the form of tube feeding and maintenance of oral hygiene to take them through the turbulent curative intent radical treatment.

In spite of the inherent demerits of the retrospective nature of the study, this study, to our knowledge, is the first one to look into the toxicities of adjuvant treatment in OSCC patients with SMF. Based on these observations, we recommend for a prospective study on this subject.

Acknowledgement

Mr. Sanjay Talole, for his valuable support in statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol 2006;42:561-8.  Back to cited text no. 1
    
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Rajendran R. Oral submucous fibrosis: Etiology, pathogenesis, and future research. Bull World Health Organ 1994;72:985-96.  Back to cited text no. 2
    
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Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epidemiol 1985;13:340-1.  Back to cited text no. 3
    
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Chaturvedi P, Vaishampayan SS, Nair S, Nair D, Agarwal JP, Kane SV, et al. Oral squamous cell carcinoma arising in background of oral submucous fibrosis: A clinicopathologically distinct disease. Head Neck 2013;35:1404-9.  Back to cited text no. 4
    
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Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.  Back to cited text no. 5
    
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Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Mehta FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984;92:224-9.  Back to cited text no. 6
    
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Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6.  Back to cited text no. 7
    
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Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44.  Back to cited text no. 8
    
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Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-52.  Back to cited text no. 9
    
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Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, et al. Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100 9 Suppl: 1995-2025.  Back to cited text no. 10
    
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Sreebny LM. Saliva in health and disease: An appraisal and update. Int Dent J 2000;50:140-61.  Back to cited text no. 11
    
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Vissink A, Kalicharan D, S-Gravenmade EJ, Jongebloed WL, Ligeon EE, Nieuwenhuis P, et al. Acute irradiation effects on morphology and function of rat submandibular glands. J Oral Pathol Med 1991;20:449-56.  Back to cited text no. 12
    
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Epstein JB, Robertson M, Emerton S, Phillips N, Stevenson-Moore P. Quality of life and oral function in patients treated with radiation therapy for head and neck cancer. Head Neck 2001;23:389-98.  Back to cited text no. 13
    
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Franzén L, Funegård U, Ericson T, Henriksson R. Parotid gland function during and following radiotherapy of malignancies in the head and neck. A consecutive study of salivary flow and patient discomfort. Eur J Cancer 1992;28:457-62.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]



 

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