|Year : 2016 | Volume
| Issue : 2 | Page : 63-68
Patterns of failure and prognostic factors for radically treated patients of oropharyngeal cancers planned by two-dimensional radiotherapy: An audit from a regional cancer center
Pragyat Thakur, Bhavana Rai, Raviteja Miriyala, Sushmita Ghoshal
Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
|Date of Web Publication||20-Dec-2016|
Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh
Source of Support: None, Conflict of Interest: None
Objectives: To review the patterns of failure and analyze various prognostic factors influencing the outcomes of radically treated patients of oropharyngeal squamous cell cancer treated at our institute with two-dimensional planning (2D). Materials and Methods: Case records of 100 oropharyngeal squamous cell cancers, which were treated radically with radiation or concurrent chemoradiation to an equivalent dose of 66 Gy in conventional fractionation, in our department between 2011 and 2013 were retrospectively analyzed for locoregional control (LRC), progression-free survival (PFS), patterns of failure, and various prognostic factors. Results: Median age of presentation was 53 years, 95% being males. Ninety-three percent had a history of tobacco use. Base of tongue was the most common site in 63% of patients followed by tonsil in 26%. All patients were of Stage III and IV. Among these patients, 27% received concurrent chemoradiation while others received radical radiation. At a median follow-up of 28 months, 57% of the patients were disease free and the LRC was 60%. Among the recurrences, 17% had local failures while 23% had nodal failures as the first site of recurrence. There were no marginal failures. On multivariate analysis, stage of the disease was the single most important prognostic factor determining the PFS and LRC. Conclusion: Stage appears to be the most important prognostic factor affecting LRC and PFS. Absence of marginal failures in our study implies adequacy of coverage with 2D treatment planning while in-field failures mandate attempts to use increased dose, chemosensitizers or nodal dissection postradical radiation.
Keywords: Locoregional control, oropharynx, prognostic factor, progression-free survival, radiotherapy, univariate analysis
|How to cite this article:|
Thakur P, Rai B, Miriyala R, Ghoshal S. Patterns of failure and prognostic factors for radically treated patients of oropharyngeal cancers planned by two-dimensional radiotherapy: An audit from a regional cancer center. J Head Neck Physicians Surg 2016;4:63-8
|How to cite this URL:|
Thakur P, Rai B, Miriyala R, Ghoshal S. Patterns of failure and prognostic factors for radically treated patients of oropharyngeal cancers planned by two-dimensional radiotherapy: An audit from a regional cancer center. J Head Neck Physicians Surg [serial online] 2016 [cited 2019 Mar 18];4:63-8. Available from: http://www.jhnps.org/text.asp?2016/4/2/63/196226
| Introduction|| |
Head and neck squamous cell carcinoma (HNSCC) is common with more than 550,000 new cases reported worldwide each year.  Oropharyngeal squamous cell cancers form the bulk of these patients, especially in developing countries including India.  Worldwide age-adjusted incidence rates for oropharyngeal cancers in men and women are 3.8 and 0.8 per 100,000 populations', respectively.  In India, the age-adjusted incidence rates in several population-based registries are among the highest in the world.  More than 60% of these patients present in locally advanced nonmetastatic stage. 
Radical radiotherapy forms the backbone of treatment in these patients with the addition of chemotherapy as a radiosensitizer if feasible, considering mainly their general condition. Intensity-modulated radiotherapy (IMRT) is now being used increasingly to treat these patients; however, two-dimensional (2D) conventional planning still remains the mainstay in many institutes of developing countries with high patient load and limited resources.
Most of the results of treatment outcome in locally advanced oropharyngeal cancers have been published in Western literature with very few publications originating from developing countries where the bulk of this subset exists. The patient characteristics and tumor biology may significantly vary in developing countries and different ethnicity; hence prognostic factors and result of treatment, as outlined in Western literature, may not hold true in our scenario. Considering this, we conducted a retrospective analysis of patients attending our outdoor patient department with locally advanced oropharyngeal cancers who were treated with a radical dose of 2D conventional radiation, to see their outcome and the prognostic factors influencing the outcome.
| Materials and Methods|| |
Between January 2011 and January 2013, 100 patients with histologically confirmed nonmetastatic locally advanced squamous cell carcinoma of oropharynx who were registered to be treated at Postgraduate Institute of Medical Education and Research with a radical dose of radiotherapy were identified from our database. The hospital case notes and radiotherapy records were obtained for retrospective review. Each patient had been reviewed by a senior faculty. Workup of the patients included detailed physical examination, routine blood investigation, fiber-optic nasal endoscopy, contrast-enhanced computed tomography (CECT) base of skull to T4 vertebra, and chest X-ray. Other investigations including CECT thorax were ordered if clinically relevant. Patients were staged at the time of initial assessment according to the 2007 tumor-node-metastasis staging system of the American Joint Committee on Cancer (AJCC). 
All patients were immobilized in supine position using individual neck support and thermoplastic cast. Patients were planned in conventional X-ray simulator. All patients were treated with megavoltage beams (cobalt or 6 MV linear accelerator) by two parallel opposed and one lower anterior fields. Radiation was used in conventional fractionation to a dose of 66 Gy (Gray) in 33 fractions (#) over 6.5 weeks. Spinal cord shielding was done after 40 Gy/20#/4 weeks as per departmental protocol. Posterior neck boost with appropriate energy electrons was added depending on pretreatment nodal extent.
Chemotherapy was added concurrently to radiation in selected patients depending on age and performance status. Cisplatin was used as a chemotherapeutic agent in a dose of 100 mg/m 2 divided over 2 days every 3 weeks.
Assessment and follow-up schedule
Patients were assessed weekly for toxicities during treatment. Radiotherapy-induced toxicity was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer acute and late morbidity scoring criteria. 
Posttreatment patients were followed up every 2 months for the 1 st year and three to four monthly in the 2 nd year. Tumor response was clinically assessed at first follow-up and documented as complete response (no clinical evidence of disease), partial response (≥50% reduction in disease burden), stable disease (<50% response reduction in disease burden), and progressive disease was defined as increase in disease at any site or appearance of new lesions. Failures were defined as regional if recurrence or persistence of disease was only at the primary site, locoregional was defined as recurrence of persistence of disease in draining lymph nodes with or without disease at primary site, and distant failure was defined as failure to distant site irrespective of failure to local area.
Prognostic factors considered included patient related, disease related, and treatment related. Patient-related factors were age, sex, use of tobacco, performance status, and pretreatment hemoglobin. Disease-related factors included the subsite involved, grade of tumor, T-stage, N-stage, number of nodal regions involved, level of lymph nodes involved, and overall stage. Treatment-related factors included treatment modality and overall treatment time (OTT).
Regional failure was defined as persistence or reappearance of disease in primary site and locoregional failure (LRF) was defined as persistence or reappearance of disease in draining lymph nodes with or without the involvement of primary site. Progression-free survival (PFS) and locoregional control (LRC) were defined from the date of start of treatment. PFS and LRC were calculated using Kaplan-Meier analysis. Univariate analysis was done with ANOVA whereas Cox-regression analysis was used for multivariate analysis. All analyses were done using the statistical package SPSS version 17.0 (SPPS Inc., Chicago, IL, USA).
| Results|| |
Patient and disease characteristics
One hundred locally advanced oropharyngeal cancer patients treated with radical radiotherapy were analyzed. Patient characteristics are defined in [Table 1] and disease characteristics are defined in [Table 2].
The median age of patients was 53 years (range, 32-70). Most of the patients were males (95%). History of tobacco addiction was present in 93.3% patients, with smoking as the most common form. Most of the smokers were heavy smokers with a median smoking index of 500. Most of the patients (83%) had Karnofsky performance status of 70. The most common subsite of involvement was base of tongue followed by tonsil. Most of the patients (70%) had T3 or T4 disease. Clinical node enlargement was seen in 64% of patients. All patients were stage III and IV. All patients had histologically proven squamous cell carcinoma.
Patients were treated with radical radiation with or without concomitant chemotherapy. Majority of the patients received radical radiotherapy alone (73%). OTT ranged from 31 days to 82 days with a median of 50 days. OTT exceeded 50 days in 42.6% of patients without any planned treatment breaks. There was no planned treatment for salvage; however, patients were individualized for surgery, palliative chemotherapy, or best supportive care although it was not analyzed in the present study.
Patients were assessed for response at first follow-up, 6-8 weeks after treatment. At first follow-up, complete response was seen in 95% of patients while residual disease was seen in 5% of patients. Median duration of follow-up was 28 months while mean duration was 29 months. At last follow-up, 57% of patients still had complete control while 43% had a failure; out of these, 17% patients had local failure and 23% patients had LRF whereas 3% patients had distant failure. Out of the LRFs, 52.2% had isolated nodal failures whereas rest had both nodal and local failure at the primary site.
No marginal failures were seen, all the failures were within field or distant. Isolated nodal failures without local failure were found in the same group of nodes which were involved initially.
LRC at median follow-up was 60% whereas PFS was 57%; however, median LRC and PFS were yet to be achieved. Kaplan-Meier analysis for PFS and LRC is shown in [Figure 1] and [Figure 2], respectively.
|Figure 1: Kaplan-Meier analysis for progression-free survival (original)|
Click here to view
Acute mucosal and skin toxicity was only documented. Twenty-one percent of patients had Grade III mucosal toxicity whereas 19% of patients had grade III skin toxicity. No patient had Grade IV mucosal or skin toxicity.
The impact of different prognostic factors was seen on LRC and PFS. Univariate analysis has been tabulated in [Table 3]. Various factors found significant on univariate analysis were T-stage, N-stage, overall stage, grade of tumor, number of nodal regions involved, and involvement of nodal region beyond level II. However, on multivariate analysis, overall stage was the only significant prognostic factor.
| Discussion|| |
Head and neck cancers are widely prevalent in developing countries including India; this can be attributed to various causes, especially widespread use of smoked and chewed tobacco. Oropharyngeal cancers form the bulk of head and neck cancers, and most of them are locally advanced at presentation.  Being locally advanced radiotherapy forms the mainstay of treatment with or without the addition of chemotherapy, in our department. Various recent advances in radiation delivery technique including IMRT and image-guided radiotherapy are increasingly being used; however, they have their share of pitfalls including increased risk of marginal miss, inhomogeneous dose distribution, increased cost, labor intensive, and increased integral dose.  Thus, to use IMRT in all patients coming to a high volume center is not feasible; moreover, most of the centers in developing countries still use cobalt teletherapy units as the main source of delivery of radiation. Considering this, we only analyzed patients of locally advanced oropharyngeal cancers treated with 2D radiation at our center. Our result of radiation therapy corresponds to other studies which have shown a 3-year LRC of around 42% and PFS of around 40%, signifying its adequacy. ,,,,
Various patient-related, disease-related, and treatment-related prognostic factors were analyzed using univariate and multivariate analysis for LRC and PFS. No patient-related factor was found significant; however age, performance status, , gender, , pretreatment hemoglobin, ,, and smoking  have been found to be of significance in various other studies. Smoking was not found significant, probably, because 93% of the patients in this analysis were smokers. Gender was not found significant because only five patients were female.
Disease-related factors including T-stage, N-stage, overall stage, grade of tumor, number of nodal regions, and involvement of lymph nodes beyond level II were found to be significant prognostic factors on univariate analysis. T-stage and N-stage have been found to be of significance in various trials. ,, the number of nodes has been widely recognized as a prognostic factor and hence is also included in the AJCC staging. The number of positive cervical lymph nodes consistently correlates with survival in univariate analysis for all major sites of HNSCC. , The anatomic location of positive cervical lymph nodes has been classically described by dividing the neck into five anatomic levels.  First echelon of lymph nodes for oropharyngeal cancers is level II lymph nodes. Mamelle et al. found that the presence of nodal metastases outside the first echelon region independently decreased 5-year survival by more than 50% and nearly doubled the rate of distant metastasis.  In our analysis, also involvement of nodal region beyond level II was significantly associated with poorer PFS and LRC.
Out of various treatment-related factors analyzed OTT, especially more than 50 days was significant. Significance of OTT has been reported in various trials. ,,, This consolidates the concept of completing treatment in time; hence, our emphasis should be on avoiding unplanned treatment breaks at all costs. Many of our patients had an OTT exceeding 50 days, and this was mainly due to noncompliance or poor tolerance.
Overall stage was the only factor which was found significant on multivariate analysis for PFS and LRC.
According to our departmental protocol, some modifications were noted in treatment including reducing the posterior field to off-cord position at 40 Gy/20#/4 weeks whereas it is otherwise done at 44 Gy/22#, this was done as we are not using compensators which lead to hot spot anteriorly leading to increased skin toxicity. Another modification is to keep the superior border in cases of node-negative base of tongue tumors to lower border of zygomatic arch thereby not only reducing mucosal toxicity but also missing the retropharyngeal group of lymph nodes. All the patients were hence also analyzed for any marginal failures, and it was found that 40% of patients had LRF; however, no patient had out of field failure thereby signifying the adequacy of treatment portals applied. Majority of nodal failures signify the lack of neck dissection postradical chemoradiation which may be due to lack of surgical oncologist at our institute. As most of the failures in head and neck tumors occur within 2 years of treatment, our median follow-up of 28 months is probably adequate to comment on marginal failures. Acute Grade III mucosal toxicity of 21% and Grade III skin toxicity of 19% were comparable to similar studies. 
Concurrent chemoradiotherapy was received by only 27% of patients. This was due to various reasons including low performance status, patients of low socioeconomic background, poor nutrition status, poor oro-dental hygiene practice which leads to increased mucositis, patients coming from far-flung areas without any proper place to stay and to cook home meals, during the course of radiation, leading to further poor nutrition, and poor tolerance of the concurrent schedule. These reasons preclude the use concurrent chemoradiation in most of these patients. No comparison among patients receiving radiation alone versus chemoradiation was performed as we did not consider retrospective data to be robust enough for such comparison, and moreover, chemoradiation was given to patients with better performance status and nutritional status which was a source of selection bias.
Shortcomings of this study include it being a retrospective analysis, all patients were not on regular follow-up due to various reasons including socioeconomic, literacy, and distance from the institute. Late toxicities including xerostomia were not well documented in case records. Specific questions about health-related quality of life were not addressed.
| Conclusion|| |
Stage appears to be the most important prognostic factor affecting LRC and PFS. Absence of marginal failures in our study implies adequacy of coverage with our modified 2D treatment planning while in-field failures mandate attempts to use increased dose, chemosensitizers, or nodal dissection postradical radiation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. Ver. 2.0. IARC Cancer Base No. 5. Lyon: IARC Press; 2004.
Kulkarni MR. Head and neck cancer burden in India. Int J Head Neck Surg 2013;4:35.
National Cancer Registry Programme (ICMR). Consolidated Report of Population Based Cancer Registries: 2004-2005. Bangalore, India; 2008.
Brizel DM. The role of combined radiotherapy and chemotherapy in the management of locally advanced squamous carcinoma of head and neck. In: Halperin EC, Perez CA, Brady LW, editors. Philadelphia: Principles and Practice of Radiation Oncology. Lippincott Williams and Wilkins; 2008. p. 807-19.
Pharynx and Larynx. In: Edge SB, Byrd DR, Compton CC. AJCC cancer staging Manual. 7 th
ed. New York: Springer; 2010. p. 41-67.
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.
Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al.
Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76.
Mendenhall WM, Amdur RJ, Palta JR. Intensity-modulated radiotherapy in the standard management of head and neck cancer: Promises and pitfalls. J Clin Oncol 2006;24:2618-23.
Jaulerry C, Rodriguez J, Brunin F, Mosseri V, Pontvert D, Brugere J, et al.
Results of radiation therapy in carcinoma of the base of the tongue. The Curie Institute experience with about 166 cases. Cancer 1991;67:1532-8.
Perez CA, Patel MM, Chao KS, Simpson JR, Sessions D, Spector GJ, et al.
Carcinoma of the tonsillar fossa: Prognostic factors and long-term therapy outcome. Int J Radiat Oncol Biol Phys 1998;42:1077-84.
Johansen LV, Grau C, Overgaard J. Squamous cell carcinoma of the oropharynx - An analysis of treatment results in 289 consecutive patients. Acta Oncol 2000;39:985-94.
Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Malyapa RS, Werning JW, et al.
Definitive radiotherapy for tonsillar squamous cell carcinoma. Am J Clin Oncol 2006;29:290-7.
Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Werning JW, Villaret DB. Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 2006;29:32-9.
Cooper JS, Farnan NC, Asbell SO, Rotman M, Marcial V, Fu KK, et al.
Recursive partitioning analysis of 2105 patients treated in Radiation Therapy Oncology Group studies of head and neck cancer. Cancer 1996;77:1905-11.
Jeremic B, Milicic B. Pretreatment prognostic factors of local recurrence-free survival in locally advanced squamous cell carcinoma of the head and neck treated with radiation therapy with or without concurrent chemotherapy. Am J Clin Oncol 2008;31:213-8.
Lee WR, Berkey B, Marcial V, Fu KK, Cooper JS, Vikram B, et al.
Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: A secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys 1998;42:1069-75.
Daly T, Poulsen MG, Denham JW, Peters LJ, Lamb DS, Krawitz H, et al.
The effect of anaemia on efficacy and normal tissue toxicity following radiotherapy for locally advanced squamous cell carcinoma of the head and neck. Radiother Oncol 2003;68:113-22.
Schäfer U, Micke O, Müller SB, Schüller P, Willich N. Hemoglobin as an independent prognostic factor in the radiotherapy of head and neck tumors. Strahlenther Onkol 2003;179:527-34.
Agarwal JP, Mallick I, Bhutani R, Ghosh-Laskar S, Gupta T, Budrukkar A, et al.
Prognostic factors in oropharyngeal cancer - Analysis of 627 cases receiving definitive radiotherapy. Acta Oncol 2009;48:1026-33.
Lee WR, Mendenhall WM, Parsons JT, Million RR, Cassisi NJ, Stringer SP. Carcinoma of the tonsillar region: A multivariate analysis of 243 patients treated with radical radiotherapy. Head Neck 1993;15:283-8.
Mak-Kregar S, Baris G, Lebesque JV, Balm AJ, Hart AA, Hilgers FJ. Radiotherapy of tonsillar and base of the tongue carcinoma. Prediction of local control. Eur J Cancer B Oral Oncol 1993;29B: 119-25.
Hannisdal K, Boysen M, Evensen JF. Different prognostic indices in 310 patients with tonsillar carcinomas. Head Neck 2003;25:123-31.
O'Brien CJ, Smith JW, Soong SJ, Urist MM, Maddox WA. Neck dissection with and without radiotherapy: Prognostic factors, patterns of recurrence, and survival. Am J Surg 1986;152:456-63.
Trible WM, Dias A. Cervical lymph node metastases. Prognosis related to level and distribution. Arch Otolaryngol 1964;79:247-9.
Spiro RH, Alfonso AE, Farr HW, Strong EW. Cervical node metastasis from epidermoid carcinoma of the oral cavity and oropharynx. A critical assessment of current staging. Am J Surg 1974;128:562-7.
Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A, Bosq J. Lymph node prognostic factors in head and neck squamous cell carcinomas. Am J Surg 1994;168:494-8.
Johansen LV, Overgaard J, Overgaard M, Birkler N, Fisker A. Squamous cell carcinoma of the oropharynx: An analysis of 213 consecutive patients scheduled for primary radiotherapy. Laryngoscope 1990;100:985-90.
van Putten WL, van der Sangen MJ, Hoekstra CJ, Levendag PC. Dose, fractionation and overall treatment time in radiation therapy - The effects on local control for cancer of the larynx. Radiother Oncol 1994;30:97-108.
Withers HR, Peters LJ, Taylor JM, Owen JB, Morrison WH, Schultheiss TE, et al.
Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions. Int J Radiat Oncol Biol Phys 1995;33:549-62.
Hoffstetter S, Marchal C, Peiffert D, Luporsi E, Lapeyre M, Pernot M, et al.
Treatment duration as a prognostic factor for local control and survival in epidermoid carcinomas of the tonsillar region treated by combined external beam irradiation and brachytherapy. Radiother Oncol 1997;45:141-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]