|Year : 2019 | Volume
| Issue : 3 | Page : 122-129
Analysis of prognostic factors and patterns of failure in patients of oropharyngeal squamous cell carcinoma treated by definitive radiotherapy in a tertiary care cancer center of Northern India
Sankalp Singh1, Nishant Lohia1, Sharad Bhatnagar1, Pankaj Kumar Sahu2, Manoj Prashar3, Sundaram Viswanath3, Subramananiam Anand4, S Harish4, Gaurav Trivedi1
1 Department of Radiation Oncology, Command Hospital (CC), Lucknow, Uttar Pradesh, India
2 Department of ENT and Head and Neck Cancer, Command Hospital (CC), Lucknow, Uttar Pradesh, India
3 Department of Medical Oncology, Command Hospital (CC), Lucknow, Uttar Pradesh, India
4 Department of Surgical Oncology, Command Hospital (CC), Lucknow, Uttar Pradesh, India
|Date of Submission||26-Jul-2019|
|Date of Acceptance||30-Aug-2019|
|Date of Web Publication||15-Oct-2019|
Dr. Nishant Lohia
Command Hospital (CC), Lucknow - 226 002, Uttar Pradesh
Background: The incidence of oropharyngeal carcinoma is increasing despite decline in the incidence of head and neck cancers of other sites. Functional organ preservation with minimal toxicity and better survival is the management goal in oropharyngeal cancers (OPCs). Morbidity of surgery favors radiotherapy as primary modality in OPCs. Here, we have reviewed and analyzed various prognostic factors and results of conventional radiotherapy in patients treated at our institute with two-dimensional planning. Materials and Methods: The records of 70 patients who were treated radically with radiotherapy with or without concurrent chemotherapy from January 2014 to May 2018 were analyzed in our institute. Results: The median age was 61.5 years with male:female ratio of 6:1. History of tobacco use was present in 83%. Stage IVA comprised the bulk with 63% of cases. Eighty-one percent of the patients received concurrent cisplatin. Median disease-free survival at 1 and 5 years was 71.4% and 54.3%, respectively. Median overall survival at 1 and 5 years was 74.3% and 60%, respectively. Conclusion: Varied patient-related, tumor-related, and treatment-related factors determine the clinical severity and tumor stage and help in predicting survival in oropharyngeal carcinoma.
Keywords: Disease-free survival, oropharyngeal carcinoma, prognostic factors
|How to cite this article:|
Singh S, Lohia N, Bhatnagar S, Sahu PK, Prashar M, Viswanath S, Anand S, Harish S, Trivedi G. Analysis of prognostic factors and patterns of failure in patients of oropharyngeal squamous cell carcinoma treated by definitive radiotherapy in a tertiary care cancer center of Northern India. SRM J Res Dent Sci 2019;10:122-9
|How to cite this URL:|
Singh S, Lohia N, Bhatnagar S, Sahu PK, Prashar M, Viswanath S, Anand S, Harish S, Trivedi G. Analysis of prognostic factors and patterns of failure in patients of oropharyngeal squamous cell carcinoma treated by definitive radiotherapy in a tertiary care cancer center of Northern India. SRM J Res Dent Sci [serial online] 2019 [cited 2020 Jan 21];10:122-9. Available from: http://www.srmjrds.in/text.asp?2019/10/3/122/269219
| Introduction|| |
A total of 834,860 new cases of head and neck squamous cell carcinoma (SCC) were reported worldwide in 2018, with nearly 2 lakh of them occurring in India. Oropharyngeal cancers (OPCs) comprise nearly 10% of them. Ninety-five percent of all tumors arising within the oropharynx are of squamous cell variety. Worldwide, the age-adjusted incidence rates for men and women with OPC are 1.8 and 0.4/100,000 populations, respectively. The age-adjusted incidence rates in Indians are among the highest in the world as per se veral population-based registries.
While traditionally it is a disease of older men, over the past few decades, there is a gradual upsurge in the incidence of OPCs in younger patients. Men are afflicted 3–5 times more often than women. Although tobacco use and alcohol continue to be the classic etiologic factors in the older population, in the younger nonsmokers and nondrinkers and predominantly among men, the cause can be attributed to infection by oncogenic human papillomaviruses (HPVs), most probably by high-risk sexual behavior. Current estimates suggest that by 2020, the annual number of HPV-positive OPCs will exceed the annual number of HPV-positive uterine cervix carcinomas and there will be more than 15,000 cases of HPV-positive OPC per year by 2030.
The oropharynx is contiguous with the oral cavity anteriorly, the larynx and hypopharynx posterior/inferiorly, and the nasopharynx superiorly. Three main subregions compose the oropharynx, including the tonsil, base of tongue, and soft palate. Approximately 70% of the patients present with nodal involvement, and 10%–15% of these have distant metastases.
Radiotherapy with or without concurrent platinum-based chemotherapy is the most preferred treatment modality for both early and advanced lesions. Conventionally, the preferred treatment for patients with Stages T1 and T2 oropharyngeal SCCs has been radiation therapy. However, advent of newer transoral surgical techniques, including lasers and robotic-assisted surgeries, has diminished morbidity and improved recovery time of surgery, making it a viable alternative to radiotherapy in very early-stage OPCs. Most of the Indian patients present in a locally advanced stage, and hence, radical radiotherapy forms the backbone of treatment with the addition of concurrent chemotherapy as a radiosensitizer if feasible based on patient's general condition.
There is a plethora of published literature on OPC from the western world. There is a substantial variation in patient-related and tumor-related factors and outcomes between the developed world where HPV associated OPC predominates and developing countries like India, where tobacco use is still the primary causative agent for OPCs. The aim of our study was to bridge this knowledge gap and to identify patient-related, tumor-related, and treatment-related factors that had an impact on outcome of this disease in an Indian population.
| Materials and Methods|| |
The investigation, treatment, and follow-up records from oncology database of our institute were retrospectively analyzed for patients with histologically confirmed nonmetastatic SCC of oropharynx treated between January 2014 and January 2018 using radiotherapy with curative intent and who had a minimum follow-up of 12 months or died before that. Statistical analysis of patient and tumor variables was carried out to identify their impact on overall survival (OS) and disease-free survival (DFS) at 1 and 3 years after treatment completion.
All patients at our center were evaluated as per the standard guidelines using clinical examination, hematological and biochemical tests, cross-sectional imaging (computed tomography [CT]/magnetic resonance imaging/positron emission tomography-CT), and histopathological diagnosis and were staged as per the 2007 Tumor-Node-Metastasis Staging System of the American Joint Committee on Cancer (AJCC).
All patients were treated with megavoltage beams on telecobalt by two parallel opposed fields. Radiation was used in conventional fractionation to a dose of 66–70 Gy in 33–35 fractions (#) over 6.5–7 weeks. Spinal cord shielding was done after 46 Gy/23#. The concurrent chemotherapy used was cisplatin 35–40 mg/m2 given weekly.
Patients were evaluated for disease recurrence (local and distant) every 3 months for the 1st 2 years and every 6 months after that. The OS and DFS of the study population were assessed at the end of 1 and 3 years after diagnosis. Percentage of the patients alive and disease-free at 1 and 3 years was also calculated.
The patient-related variables that were studied were age, gender, history of tobacco use, and presence of comorbidities. Patients were defined as having comorbid illness if they had preexisting diagnoses of any one or more of diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, and tuberculosis. The clinical variables included tumor site, tumor (T) stage, nodal (N) stage, and composite clinical stage. The pathological variable included was tumor grade (well, moderately, or poorly differentiated). The total duration of radiotherapy treatment and the use of concurrent chemotherapy were the treatment-related variables studied.
Mean periods of OS and DFS were estimated by Kaplan–Meier curves. Association of varied patient-related, tumor-related, and treatment-related factors with outcome measures (OS and DFS) was estimated using Pearson's Chi-square test.
| Results|| |
The distribution of study subjects as per various demographic, tumor and treatment variables is given at [Table 1]. The age of the patients ranged from 38 to 80 years, with a median age of 60.5 years. Base of tongue was the most common subsite, followed by tonsil, vallecula, and soft palate. Tobacco use was seen in 83% of cases. Majority of the patients presented in Stage IVA with 77% of the patients having clinically evident nodal metastases. As for histological grade of tumors, 44% were moderately differentiated, 29% were poorly differentiated, while 27% were well differentiated.
|Table 1: Distribution of patient, disease, and treatment variables in the study population|
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The OS and DFS rates at 1, 2, and 3 years of follow-up for the entire population as well as their distribution for various study parameters are given in [Table 2] and [Table 3], respectively.
[Table 4] shows the percentage of patients who were alive and of those who were disease-free at 1 and 3 years, respectively.
|Table 4: Percentage of patients who were alive and of those who were disease-free at 1 and 3 years, respectively|
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Similarly, the mean DFS and OS at 1 and 3 years are given, respectively, in [Figure 1]a, [Figure 1]b and [Figure 2]a, [Figure 2]b, respectively.
|Figure 1:(a) Disease-free survival at 1 year, (b) disease-free survival at 3 years|
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|Figure 2:(a) Overall survival at 1 year, (b) overall survival at 3 years|
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As can be seen in [Table 2] and [Table 3], the presence of comorbidities negatively impacted both OS and DFS in a statistically significant manner. Although grades of tumor had no significant correlation with OS, statistically significant correlation was seen with DFS with well-differentiated tumor, showing lesser recurrences as compared to poorly and moderately differentiated tumors.
The rest of the study parameters did not show a statistically significant correlation with the study outcomes. However, certain trends were observed. Young patients, females, and nontobacco users had better survival outcomes compared to elderly, male sex, and tobacco abusers. DFS and OS were also better for patient who had disease localized to tonsil and vallecula compared to those with OPC of the base of tongue. Similarly, patients who received concurrent chemotherapy fared marginally better than those who did not receive chemotherapy of any sort [Table 2] and [Table 3].
As the majority of the study population (>80%) was in Stage IV at presentation, the effect of T, N, and group staging could not be evaluated satisfactorily.
| Discussion|| |
Although HPV has been identified as an emerging cause of OPC in the Western world, in India, the widespread tobacco consumption in both smoked and smokeless forms remains the primary etiological factor for this disease. Even in our study, around 83% subjects had positive history of tobacco use for more than 1 year during their lifetime. Moreover, HPV-associated OPC is seen in a younger population, while we had only four patients who presented with this disease before the age of 50 years. The vast majority (94%) were more than 50 years of age and nearly half (46%) were above the age of 65 years. Men everywhere in the world have a 2–5-fold greater risk of head and neck cancer (HNC) than women and similar trend was seen here. This difference can be directly attributed to various sociocultural factors, leading to a higher prevalence of tobacco and alcohol usage among men than women. We too in our study had significantly more males than females, with a sex ratio of 6:1. Johnson et al. found that “male patients are more likely to present at a late stage compared with female patients.” They attributed the association between late stage presentation with differences in attitudes toward screening examinations or differences in willingness to bring symptoms to medical attention.
In India, OPCs are the third most common type of HNC after oral cavity and larynx. Nearly, all of them are locally advanced at presentation as has also been seen in our study (95%). While sociocultural factors such as lack of disease awareness among the general population and lack of access to adequate diagnostic facilities contribute to this phenomenon of late presentation of OPCs,, another reason is the disease biology. Due to lack of visual access to the region, as well as lack of early symptoms, oropharyngeal tumors remain undetected until they involve surrounding structures or spread to the draining lymphatics, resulting in early nodal metastases.
The standard curative treatment for OPC is radical radiotherapy with or without concurrent chemotherapy and surgery in very early stage if feasible. Recent advances in radiotherapy techniques with advent of intensity-modulated radiotherapy also have their share of pitfalls such as risk of marginal miss, labor intensivity, increased cost, inhomogeneous dose distribution, and increased integral dose. Thus, most of the centers in developing countries still use cobalt teletherapy units as the main modality of radiation delivery. We too use the same technology and analyze patients of OPCs treated with two-dimensional (2D) radiation at our center. Our result of radiation therapy corresponds to other studies and has shown a 3-year OS and DFS of 61.4% and 51.75, respectively. This is significantly lower than the survival and DFS rates of oral cavity cancer at our own center, reflecting the poorer outcome and prognosis in OPCs compared to oral cavity cancer.
Various patient-related, disease-related, and treatment-related prognostic factors were analyzed using univariate analysis. No patient-related factors were significant, except the presence of comorbidities. Patients with any of the concurrent comorbidities had a significantly poorer outcome than those without any. This might be a reflection of the poorer general and medical condition of the patient while also might be a reason for poorer performance status and treatment tolerance of the patient, leading to inadequate therapy and resulting in the poorer results. Many studies have also shown significant correlation of elderly age, male gender and tobacco use with worse outcome., Similar trends were seen in our study population though the differences were not statistically significant. Among the disease related factors in our research, only histological grade of tumor had significant correlation with DFS which was78.9% in WDSCC compared to 55% in PDSCC at the end of 3 years. However, the prognostic significance of grade independently is difficult to ascertain due to wide variation in pathological interpretation and patient characteristics. Similarly, many trials have found T and N-stage to be of prognostic significance.,, and the number of nodes has been widely recognized as a prognostic factor and hence is also included in the AJCC staging. The lack of significance with other disease related factors in our study might be attributed to lack of large enough sample size.
For patients with locoregionally advanced OPC, concurrent chemotherapy is the standard treatment and is based on the results of the meta-analysis of HNC, which demonstrated a 6.2% absolute improvement in OS at 5 years from the use of concurrent chemoradiotherapy compared to radiotherapy alone. Though the difference was statistically not significant, but even in our study patients who received concurrent chemotherapy along with radiotherapy had better survival rates as compared to those patients who received radiotherapy alone without chemotherapy. Although duration of radiotherapy was also assessed to see impact on outcome, no significant outcome could be assessed.
Thirteen patients had local recurrence, six had nodal recurrence, and ten had distant recurrence at end of 3 years. Of the six nodal recurrences, one patient had only isolated nodal recurrence at end of 6 months of completion of radiotherapy for which he underwent neck dissection and is currently alive. Of the 13 patients who had local recurrence, the recurrence was within the high dose area of the radiation field, thereby suggesting adequate coverage with 2D radiotherapy.
| Conclusion|| |
The main cause of high mortality and morbidity in an Indian setting can be attributed to late presentation of the disease in advanced stages. Histological grades, use of chemotherapy, tobacco use, gender, and presence of comorbidities may also affect outcome of treatment.
The major shortcomings of this study are that being a retrospective study, not all patients were on regular follow-up. Moreover, HPV prevalence in the study population could not be assessed due to lack of laboratory facilities for the same. This might have been an important etiological factor, especially in nontobacco users.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
National Cancer Registry Programme. Three Year Population Based Cancer Registries 2012-2014. Bangalore: Indian Council of Medical Research; 2019.
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-36.
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al.
Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:4294-301.
Edge SB, Byrd DR, Compton CC, editors. Pharynx and larynx. In: AJCC Cancer Staging Manual. 7th
ed. New York: Springer; 2010. p. 41-67.
Lohia N, Bhatnagar S, Singh S, Prashar M, Subramananiam A, Viswanath S, et al
. Survival trends in oral cavity cancer patients treated with surgery and adjuvant radiotherapy in a tertiary center of Northern India: Where do we stand compared to the developed world? SRM J Res Dent Sci 2019;10:26-31. [Full text]
Johnson S, Corsten MJ, McDonald JT, Chun J. Socio-economic factors and stage at presentation of head and neck cancer patients in Ottawa, Canada: A logistic regression analysis. Oral Oncol 2010;46:366-8.
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.
Tripathi N, Kadam YR, Dhobale RV, Gore AD. Barriers for early detection of cancer amongst Indian rural women. South Asian J Cancer 2014;3:122-7.
] [Full text]
Pramesh CS, Badwe RA, Borthakur BB, Chandra M, Raj EH, Kannan T, et al
. Current burden and health systems in India 3-delivery of affordable and equitable cancer care in India. Lancet Oncol 2014 May; 15(6):e223-33.[Doi: 10.1016/S1470-2045 (14)70117-2].
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.
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.
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.
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.
Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]