|Year : 2015 | Volume
| Issue : 2 | Page : 364-368
Prediction of outcome in buccal cancers treated with radical radiotherapy based on the early tumor response
GV Giri, B Thejaswini, R Nanda, K Aradhana
Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, India
|Date of Web Publication||7-Jul-2015|
G V Giri
Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Hosur Road, Bangalore - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
Aim of the Study: Aim was to assess the clinical significance of the rate of tumor regression in carcinoma buccal mucosa undergoing radical radiotherapy.
Materials and Methods: Sixty six patients were enrolled in the study with proven buccal cancers requiring radical radiotherapy, from 1990 to 1996. Radiotherapy was delivered using a combination of external beam and brachytherapy with preloaded cesium 137 needles. The response to the radiation was assessed at the completion of external beam radiation and 6 weeks after brachytherapy. An analysis correlating various parameters influencing the long term disease free survival and overall survival was done.
Results: Response assessed at the end of external beam radiation correlated strongly with the overall survival and the disease free interval (P=0.000). No other factor influenced the survival.
Conclusion: The rate of the tumor regression can predict the overall outcome in patients with buccal cancers treated with radiation. Completion of the planned course of radiation in patients who do not show a substantial reduction in size by 4.5 weeks of conventional radiation does not improve the results.
Keywords: Buccal mucosa, interstitial implant, oral cavity cancers, outcome, prediction, tumor response
|How to cite this article:|
Giri G V, Thejaswini B, Nanda R, Aradhana K. Prediction of outcome in buccal cancers treated with radical radiotherapy based on the early tumor response. J Can Res Ther 2015;11:364-8
|How to cite this URL:|
Giri G V, Thejaswini B, Nanda R, Aradhana K. Prediction of outcome in buccal cancers treated with radical radiotherapy based on the early tumor response. J Can Res Ther [serial online] 2015 [cited 2017 Oct 21];11:364-8. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/364/160049
| > Introduction|| |
Carcinoma of the buccal mucosa is one of the commonest oral cavity tumors seen in India. The age adjusted rates as per the Population Based Cancer Registry  in males and females are 2.4 and 4.4, respectively. The incidence as reported by the Kidwai Memorial Institute of Oncology Hospital Based Cancer Registry  is 6% of all malignancies, constituting 27% of all head and neck cancers.
The choice of treatment in oral cavity cancers is mainly based on the functional and cosmetic outcome, and the preference of the clinician. The inherent advantage of radiation is preservation of facial cosmesis at the end of treatment, when compared to the potentially morbid surgery with reconstruction, especially with larger volume disease of the buccal mucosa. It would therefore be of benefit to be able to predict which patients will respond to a complete course of irradiation.
We present the outcome based on the tumor regression in Carcinoma Buccal Mucosa treated prospectively at our institute between the period June 1990 and June 1996 with combined external radiotherapy and 137 Cs interstitial brachytherapy. This study had both the approval of the institutional review committee and the ethical committee.
| > Materials and methods|| |
Sixty-six consecutive patients presenting with carcinoma of the buccal mucosa between the period June 1990 and June 1996 underwent external radiation on telecobalt or telecaesium, followed by interstitial implantation of the buccal. Patients included for the study had a histopathological proof of malignancy, were deemed suitable to undergo radical treatment including general anesthesia and presented with well-demarcated tumors, which on examination could be encompassed adequately by an implant. Skin tethering or minimal involvement of the gingivobuccal (GB) sulcus did not preclude radical treatment with radiation. However, patients with gross involvement of the sulcus or frank involvement of skin were excluded from the study. Patients presenting with any trismus, mandibular involvement, a general condition on assessment found not suitable to undergo radiation with radical intent or presenting with comorbid conditions that prevented administration of general anesthesia safely were also excluded from the study. Only patients with a clinically N0 presentation were undertaken for this study.
All patients underwent a dental evaluation and intervention when necessary before starting treatment. A complete hemogram and biochemistry, chest X-ray, orthopantomography, and a biopsy from the primary was done in all patients. Patients did not undergo computerized axial tomography (CAT) or an magnetic resonance imaging (MRI) during this period prior to starting treatment. Clinical staging was as per the Union of International Cancer Control TNM staging (UICC TNM)  after a measurement of the tumor in its maximum dimensions. Patients presenting with a minimal skin tethering were staged as T4 disease. A written consent was obtained from all patients prior to starting radiation.
Response to treatment was assessed during treatment and after treatment. The first evaluation was done immediately after external radiation, recorded as immediate response; and the second after 6 weeks of completion of radiation, that is, both external radiation and interstitial brachytherapy (recorded as final response). Then the patients were regularly assessed at fixed follow-up intervals.
Response to treatment was assessed as per a modified World Health Organization (WHO) response criterion.  Tumor regression if assessed as being greater than 75% of original dimensions were graded as good response. A 50-75% regression of tumor was graded as moderate and below a 50% regression was graded as a poor response. Any progression of disease was recorded, if there was more than a 25% increase in the size of the dimensions. Nonresponders or poor responders at the end of radical radiotherapy were counseled to undergo salvage surgery if feasible in conjunction with the head and neck surgeons.
Follow-up after the first 6 weeks of end of treatment was every 2 months for the first 18 months and for the next 18 months every 3 months apart. The patients after a period of 3 years were then requested to come for examination every 6 months for the next 2 years and yearly thereafter.
Disease-free survival was defined as the interval period from the date of start of external beam radiation therapy (EBRT) and recurrence of disease locally or regionally. Partial responders or nonresponders at 6 weeks after completion of radiation (final response) were deemed to have a 0 (zero) month DFS. Overall survival was calculated from the date of starting EBRT and the reported death of the patient.
External radiation was delivered by either telecobalt (SSD = 80 cm) or a telecaesium unit (Caesa-Gammatron, source-surface distance (SSD) =40 cm). An anterolateral wedge pair technique was used when treatment with telecobalt was instituted. A single ipsilateral portal with dose prescribed at a depth was planned when treating with telecaesium. Doses of 4,400-5,000 cGy/4-5 weeks, at 2Gy/fraction were the planned prescribed doses. In patients presenting with larger primaries (> 4 cm) or when there was suspicion of involvement of the dermis, the ipsilateral whole neck was included in the field of radiation. In all other situations, radiation to the lower neck was avoided.
All the patients after external radiation in this study underwent brachytherapy irrespective of the response. A single plane interstitial implantation was done with preloaded 137 Cs needles under general anesthesia. The original area of the primary with a margin was implanted percutaneously with a minimal distance of 1cm between needles. In tumors encroaching onto the GB sulcus, a needle was placed in the GB sulcus groove that ensured adequate coverage of the primary. A minimal dose of 3,000 cGy was prescribed and attempted to be delivered in all cases. Dosimetry was carried out using a TSGRAD-PLAN treatment planning system (TPS) for both external beam radiation and interstitial implantation. The dose prescribed for the implant was at the isodose line which encompassed the target volume completely.
The statistical analysis was done using the Statistical Package for Social Sciences (SPSS) version 16.0, SPSS Inc, 2007.
| > Results|| |
A total of 66 patients were studied as to the predictive value of early tumor response in the treatment outcome of carcinoma of the buccal mucosa. [Table 1] shows the patient characteristics and treatment details of these patients.
The age of the patients ranged from 23 to 76 years and there was an male: female (M: F) ratio of 1:5. Thirty-nine percent of patients presented with an early stage disease (stages 1 and 2) and 61% patients with late stage disease (stages 3 and 4). Skin tethering was considered as involvement of the dermis, and accordingly staged in six patients (9%) as T4 status in those patients characterized with late stage disease.
External radiation doses ranged from 4,400 to 5,000cGy and the gap between the ends of external radiation to brachytherapy ranged from 11 to 35 days. EBRT was delivered in forty-six patients on telecobalt, the remaining 20 patients underwent radiation on the Caesa-Gammatron. The brachytherapy dose delivered by the planar implant ranged from 2,790 to 4,000 cGy. The mean area and volume of the implant was 20.6 and 31.9 cm 3 , respectively.
The response to Radiation was assessed both at end of external radiotherapy and 6 weeks after the completion of the implantation [Table 2]. There was a 9% improvement in the status of patients who were assessed as having a moderate response to initial EBRT and subsequently after 6 weeks of completing both EBRT and brachytherapy (moderate to good). The number of poor responders essentially remained the same.
Kaplan-Meir survival curves were generated both for the disease-free interval and the overall survival as shown in [Figure 1] and [Figure 2]. The disease-free interval ranged from 6 weeks to 117 months. Follow-up was maintained meticulously and of the entire study group only one patient was deemed to have been lost after the 6-week assessment as she did not return for her 2-monthly check-up. The median follow-up in this study was 21.5 months.
A bivariate analysis showed a significant association between both immediate response and final response with the disease free status and the overall survival [Figure 3] and [Figure 4]. There was a strong correlation between immediate response to EBRT and disease free status (log rank, P = 0.000) and overall survival status (log rank, P = 0.001). A trend towards significance of association between early stage disease (T1 and T2) versus late stage (T 3 and T4) and disease-free survival was also seen (log rank, P = 0.060). However, this was not reflected on the overall survival of the patients. No other clinical- or treatment-related factor [Table 1] influencedthe disease free status or the overall survival status.
| > Discussion|| |
The purpose of this study was to predict the outcome based on the early response of tumors of the buccal mucosa treated with radical radiation. The results in our study indicate that assessment at end of initial external radiation can predict long-term outcomes. Patients, who exhibited a good tumor regression after initial radiation, had a significantly better disease-free and overall survival.
A number of studies till date have correlated various parameters predicting outcome after radiotherapy to head and neck cancers. ,,,,,, Clinically assessed tumor regression has also been regarded as a marker for radiocurablity and has been reported to be an important prognostic marker.
Sobel et al.,  from their study concluded that response to radiation could predict outcome with 50-80% accuracy in various sites of the primary in the head and neck. It was concluded that the rate of tumor regression was not accurate, but assessment of response done at the end of 1-3 months post radiation was predictive. Dawes  observed in various sites of the head and neck that when there was a complete regression at 1 st month post radiotherapy, the local failure was 24% compared to 75% if incomplete regression. At 3 months posttreatment, the local failure was 23 versus 84% when complete and incomplete regressions were compared. For carcinomas in the oral cavity, the local failure was 27 versus 93% when compared at 3 months. Bataini et al.,  in a retrospective analysis of 1,897 patients showed, depending on the location of the primary in the oropharynx and laryngopharynx, there was a local control of 75-90% in early stages and a 50-80% in late stage presentations, showing a complete tumor regression at 2 months posttreatment. It was concluded that complete tumor regression at completion of irradiation could be used as a reliable indicator for permanent local control.
In a prospective study, Jaulerry et al.,  in 228 patients observed a very significant difference in the 2-year local control rate between major responders (75-100% regression) and other responders (0 to less than 75% regression) at 5 th week of radiation. Two groups could be identified at 55 Gy, that is, major (> 75%) and minor responders (< 50%) with prognostic significance. The response at 55 Gy was independent of the primary site in the head and neck and was significant in the oral cavity, oropharynx, and larynx; but nonsignificant in the hypopharynx. The study suggested that tumor regression during external radiation was an independent prognostic factor in the control of head and neck carcinomas.
Denys et al.,  reported in a series of 62 patients with advanced head and neck cancers undergoing chemoradiotherapy, a correlation between tumor regression rates and survival. Though there was a significant difference of survival in patients showing a complete or near complete regression compared to partial or no regression, a rapid tumor regression (median = 4.2 weeks) was associated with an inferior survival outcome as compared to a slower tumor regression (median = 6.4 weeks) and it was concluded that altering treatment based on the initial tumor regression rates should be avoided. Kawashima et al.,  in their retrospective study of 70 patients of advanced head and neck cancers undergoing chemoradiation observed, complete response assessed at 6 months correlated better with survival than at 4 weeks or 3 months.
Though there is consent of the extent of regression at the end of irradiation having a bearing on the local control and survival, disagreement as to the rate of regression and the time of assessment persists. Our study concurs with the study by Jaulerry et al.  in identifying two groups based on response (good vs moderate or poor) with prognostic significance before completing a radical dose of radiotherapy. The results suggest that if there is no significant reduction in size of the tumor at the end of 4.5 weeks of radiation (46 Gy), further radiation even to high doses is unlikely to improve outcome.
| > Conclusion|| |
Predicting the long-term outcome at an early stage is advantageous for patients undergoing radiation. It is aimed at sparing patients from continuing treatment that would be ineffective and toxic on one hand and could indicate possibly altering treatment in resistant tumors. In the absence of any cost-effective, robust methods to help predict treatment outcome, tumor regression while on radiation, as a surrogate marker would be clinically useful.
| > Acknowledgment|| |
We are deeply grateful to Prof. Keshava, former Head of Department of Medical Physics, Kidwai Memorial Institute of Oncology, for the brachytherapy dose calculations and his unstinted support during this study. We also acknowledgement that there is a equal contribution in the preparation of this manuscript by Dr. Giri. G.V. and Dr. Thejaswini B. and both are to be considered as first authors for this article.
| > References|| |
Population Based Cancer Registry - Kidwai Memorial Institute of Oncology. Bangalore: Report 2010; Head and Neck Cancers.
Hospital Based Cancer Registry-Kidwai Memorial Institute of Oncology, Bangalore: Report 2010; Head and Neck Cancers.
Hermanek P, Sobin LH, Editors. The Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours. 4 th
ed. 1987. p. 16-18.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207-14.
Brock WA, Baker FL, Wike JL, Sivon SL, Peters LJ. Cellular radiosensitivity of primary head and neck squamous cell carcinomas and local tumour control. Int J Radiat Oncol Biol Phys 1990;18:1283-6.
Langer CJ. Exploring biomarkers in head and neck cancers. Cancer 2012;118:3882-92.
Brun E, Ohisson T, Erlandsson K, Kjellen E, Sandell A, Tennvall J, et al
. Strand SE- early prediction of treatment outcome in head and neck cancers with 2- 18
FDG-PET. Acta Oncol 1997;36:741-7.
Molling JW, Langius JA, Langendijk JA, Leemans CR, Bontkes HJ, Van der Vilet HJ, et al
. Low levels of circulating Invariant Natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol 2007;25:862-8.
Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D. Impact of tumour hypoxia and anemia on radiation therapy outcomes. Oncologist 2002;7:492-508.
Bjork Eriksson T, West C, Karlsson E, Mercke C. Tumour Radiosensitivity (SF 2
) is a prognostic factor for local control in Head and Neck cancers. Int J Radiat Oncol Biol Phys 2000;46:13-9.
Begg AC. Predicting recurrence after radiotherapy in head and neck cancer. Semin Radiat Oncol 2012;22:108-18.
Sobel S, Rubin P, Keller B, Poulter C. Tumour persistence as a predictor of outcome after radiation therapy of head and neck cancers. Int J Radiat Oncol Biol Phys 1976;1:873-80.
Dawes PJ. The early response of oral, oropharyngeal, hypopharyngeal and Laryngeal cancer related to local control and survival. Br J Cancer 1980;41:14-6.
Bataini JP, Jaulerry C, Brunin F, Ponvert D, Ghossein NA. Significance and therapeutic implications of tumour regression following radiotherapy in patients treated for squamous cell carcinoma of the oropharynx and pharyngolarynx. Head Neck 1990;12:41-9.
Jaulerry C, Dubray B, Brunin F, Rodriguez J, Point D, Blaszka B, et al.
Prognostic value of tumour regression during radiotherapy for head and neck cancer: A prospective study. Int J Radiat Oncol Biol Phys 1995;33:271-9.
Denys D, Kumar P, Wong FS, Newman LA, Robbins KT. The predictive value of tumour regression rates during chemoradiation therapy in patients with advanced head and neck squamous cell carcinoma. Am J Surg 1997;174:561-4.
Kawashima M, Fujii H, Hayashi R, Tahara M, Nasu K, Arahira S, et al
. Influence of delayed tumour clearance on reliability of complete response rate in chemoradiotherapy for head and neck cancer. Jpn J Clin Oncol 2007;37:559-67.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]