|Year : 2017 | Volume
| Issue : 3 | Page : 502-507
Nasopharyngeal carcinoma: Experience and treatment outcome with radical conformal radiotherapy from a tertiary care center in India
Beena Kunheri, Gunjan Agarwal, PS Sunil, Anoop Ramesan Nair, KU Pushpaja
Department of Radiotherapy, Amrita School of Medicine, Amrita Vishwa Vidyapeetham University, Kochi, Kerala, India
|Date of Web Publication||24-May-2018|
Dr. Beena Kunheri
Department of Radiotherapy, Amrita School of Medicine, Amrita Vishwa Vidyapeetham University, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
BACKGROUND AND AIM: The majority of nasopharyngeal carcinoma (NPC) reports on the outcome and prognostic factors are from endemic high-risk regions. Data on the outcome of Indian patients are sparse. In this study, we retrospectively analyzed the outcome of NPC patients treated radically with conformal radiotherapy (RT). The primary objective was to assess the outcome, and the secondary objectives were to assess treatment-related morbidities and the impact of various prognostic factors on the outcome. MATERIALS AND METHODS: Sixty-eight patients with biopsy-proven NPC who received radical conformal RT, i.e., three-dimensional conformal RT or intensity-modulated RT (IMRT) during 2004–2013 were analyzed. All patients received conformal RT with or without chemotherapy. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS, version 20.0) software, IBM, USA. Survival analysis was performed using Kaplan–Meier method. For calculating the hazard ratio of the prognostic factors, univariate and multivariate Cox regression analyses were done. Chi-square test was used to determine the association. RESULTS: In this study, with a median follow-up of 43 months, the overall survival (OS), disease-free survival, and cause-specific survival were 91, 85.2, and 98.4% at 2 years and 78.3, 72.8, and 88.2% at 3 years, respectively. The locoregional failure was low (3%), and the 5-year cause-specific survival with chemoradiation was excellent (79%), even with 50% of the patients being nonmetastatic Stage IV. Eleven out of 12 failures were distant metastases. The treatment-related late morbidities were acceptable and better with IMRT. Significant prognostic factors affecting the outcome were composite stage of the disease and the interval between diagnosis and treatment initiation. CONCLUSION: In locally-advanced NPC, excellent local control is possible with modern conformal RT with concurrent chemotherapy. Distant metastases remain a therapeutic challenge despite systemic chemotherapy. Novel systemic therapies are needed in the future for improving the OS of these patients.
Keywords: Conformal radiotherapy, CTRT, intensity-modulated radiotherapy, Nasopharyngeal carcinoma
|How to cite this article:|
Kunheri B, Agarwal G, Sunil P S, Nair AR, Pushpaja K U. Nasopharyngeal carcinoma: Experience and treatment outcome with radical conformal radiotherapy from a tertiary care center in India. Indian J Cancer 2017;54:502-7
|How to cite this URL:|
Kunheri B, Agarwal G, Sunil P S, Nair AR, Pushpaja K U. Nasopharyngeal carcinoma: Experience and treatment outcome with radical conformal radiotherapy from a tertiary care center in India. Indian J Cancer [serial online] 2017 [cited 2019 Dec 6];54:502-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/3/502/233139
| » Introduction|| |
Nasopharyngeal carcinoma (NPC) has a low incidence in India except in the northeastern region of the country. Radiotherapy (RT) is the primary treatment modality for NPC because of the anatomical location and radiosensitivity. Early-stage disease is often successfully treated with RT alone with a 5-year overall survival (OS) of 87–96% in Stages I and II. In advanced localized disease, concurrent chemoradiation followed by adjuvant chemotherapy has become the standard of care since the Intergroup trial. NPC shows a dose–response relationship, and locoregional control correlates with the total radiation dose and overall treatment time.,,,, The evolution of radiation treatment techniques from two-dimensional techniques to three-dimensional conformal RT technique (3DCRT) and then to intensity-modulated RT technique (IMRT) enabled dose escalation with acceptable morbidity. As metastatic failure poses a significant problem, appropriate sequencing of chemotherapy with radiation therapy has also been investigated to improve the outcome. Stage of the disease is an important factor in determining the outcome and other known prognostic factors that are related to the extent or bulk of the tumor.,,, Various other prognostic factors have also been studied that can have an impact on the outcome, such as age, gender, histology, circulating Epstein-Barr virus (EBV) DNA titers, estimated glomerular filtration rate expression, and other molecular biomarkers., Most of these reports are from high-risk geographical regions, and literature on the outcome of Indian patients is sparse. In this study, we retrospectively analyzed the outcome of NPC patients treated radically with conformal RT during 2004–2013.
The primary objective was to assess the clinical outcome in terms of OS, disease-free survival (DFS), and cause-specific survival (CSS) after radical treatment.
Secondary objectives were to assess the impact of various prognostic factors on the outcome and treatment-related morbidities.
| » Materials and Methods|| |
Sixty-eight patients with biopsy-proven NPC who received radical conformal RT during 2004–2013 were analyzed.
Based on the results obtained from patients receiving radical radiation therapy/radical concurrent chemoradiation therapy  with 20% allowable error and 99% confidence, minimum sample size was estimated to be 75. Of the 87 NPC cases available from the hospital records, only 68 were eligible for the analysis. All patients were staged as per the AJCC 7th edition staging system.
Management of early-stage patients included radical RT with or without concurrent chemotherapy. For patients with locally-advanced disease (Stages III, IVA, IVB), the treatment comprised radical concurrent chemoradiation therapy (CTRT) with neo-adjuvant/adjuvant chemotherapy. Decision regarding chemotherapy was taken considering stage, age, nutritional status, and biochemical parameters. Most patients were treated with IMRT, some with 3DCRT. In general, a total dose of 70 Gy/33–35# was given to the gross tumor and 50–60 Gy for elective treatment of potential risk sites. The high-risk volume comprising the primary nasopharyngeal tumor and lymphadenopathy was treated with 70 Gy with a margin of 5–10 mm, while the entire nasopharynx received 66 Gy. The intermediate risk volume comprising the high-risk volume and the potential risk sites and lymphatic regions, including the bilateral retropharyngeal nodes, bilateral levels II, III, and VA, was treated with 60 Gy. The low-risk volume comprising levels (IV–VB), upper ethmoid sinus, and the cribriform region were treated with 50–56 Gy. As this study included patients from 2004 to 2013, there were differences in dose schedules. Currently, Simultaneous Integrated Boost-IMRT protocol is followed: high risk (gross disease both primary and nodal + margin): 70 Gy/33 fractions at 212.12 cGy/Fr. Entire nasopharynx: 66 Gy/33 fractions at 200 cGy/Fr. Intermediate risk: 60 Gy/33 fractions at 181.8 cGy/Fr (nodal regions and the intermediate risk volume around the nasopharynx). Low risk: 54–56 Gy/33 fractions at 163.6 cGy/Fr. For the 3DCRT plan, the conventional fields shaped according to the target were used.
Concurrent chemotherapy schedules were: cisplatin 100 mg/m 2 every 3 weeks (D1, 22, 43) or cisplatin 40 mg/m 2 weekly for 6–7 cycles. Induction chemotherapy consisted of 100 mg/m 2 of cisplatin on D1 + 1 g/m 2 5-fluorouracil (TPF) on D1-5 every 4 weeks for 2–3 cycles, and adjuvant chemotherapy consisted of 80 mg/m 2 of cisplatin on D1 + 1 g/m 2 TPF on D1-4 every 4 weeks for 3 cycles.
Patients were assessed weekly for treatment-related toxicities. Posttreatment follow-up was done every 1–2 months in the first year, 2–4 months in the second year, 4–6 months in the 3rd to 5th year, and annually thereafter. Follow-up evaluation included clinical examination and fiberoptic nasopharyngoscopy. Serum thyroid-stimulating hormone, free T4 testing was done every 6–12 months for detecting subclinical hypothyroidism. Other investigations were performed, if clinically indicated.
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS version 20.0, for Microsoft Windows, IBM, USA) software. Kaplan–Meier estimate of survival rate was computed for the subgroups of all prognostic factors. To test the statistical significance of the difference in survival rate between various subgroups of each factor, the log-rank test was applied. For calculating the hazard ratio of the prognostic factors, univariate and multivariate Cox regression analyses were performed. Chi-square test was used to determine the association.
OS was defined as the time from the diagnosis to death resulting from any cause. Patients who were alive were classified as censored observations at the time of last follow-up. DFS was defined as the time from the diagnosis to either recurrent disease or death resulting from any cause, whichever occurred first. Second primary tumors were not counted as events in the DFS analysis. Patients who were alive without recurrence were classified as censored observations at the time of last follow-up. CSS was defined as the time from the diagnosis to death due to the index primary tumor. Patients who were alive were classified as censored observations at the time of last follow-up, and patients dying from any cause other than NPC were classified as censored observations at the time of death.
Second primary tumor was defined as any tumor that developed in a different location, nonsquamous histology, or tumor in the same region diagnosed after 60 months of the index tumor. Treatment-related toxicity was assessed using Radiation Therapy Oncology Group acute and late radiation morbidity scoring criteria. Normal tissue effects occurring/persisting more than 90 days after irradiation were scored as late toxicity. Acute hematological toxicities were assessed using the National Cancer Institute Common Toxicity Criteria CTCAE 4.03.
This study was approved by the Institutional Review Board.
| » Results|| |
Sixty-eight eligible patients were included in the analysis. Age group of our patients was in the range of 12–73 years. Most patients were in the age group 51–60 years. Patient characteristics are listed in [Table 1]. The most common histological type was nonkeratinizing squamous cell carcinoma, i.e., World Health Organization Type 2 (62 patients), and there were no Type 3 histology patients. Other histological variants were adenocarcinoma, adenoid cystic, and clear cell carcinomas. Histological grade was poorly differentiated in 53 (78%) patients. Contrast-enhanced computed tomography (CT) was performed for all patients, magnetic resonance imaging for 21, and positron emission tomography CT for 17 patients [Figure 1].
[Table 2] and [Table 3] show the different IMRT and 3DCRT regimens that were used during the treatment period from 2004 to 2013 with the biological effective dose to the tumor (BEDT). Of the 25 patients who had an RT break, 80% had the break after completing 20 fractions of radiation, mainly due to Grade 3 mucositis; four patients had coexistent neutropenia.
|Table 2: Three dimensional conformal radiotherapy dose schedule and biologically effective dose|
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|Table 3: Intensity modulated radiotherapy dose schedules and biologically effective dose|
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In our study group of 68 patients, no patient had late Grade 4 RT toxicity. Five patients developed Grade 3 toxicity that required intervention and were successfully salvaged, whereas the rest were managed conservatively. One patient had panhypopituitarism, 5 had clinical hypothyroidism, and 14 had subclinical hypothyroidism. Acute and significant late toxicities are listed in [Table 4] and [Table 5]. Nearly 91% of the patients completed 75–100% of neoadjuvant/adjuvant chemotherapy, and out of the 63 patients who had concurrent chemotherapy, 86% completed 66–100% of the intended concurrent chemotherapy.
In the study population, 12 patients had recurrence, of which 1 patient had an isolated local recurrence, 1 patient had regional nodal recurrence along with distant metastases to the bone, and the remaining 10 patients had distant metastases [Table 6] and [Table 7].
In the study population, 5 patients developed a second primary tumor and the site of the second primary was breast (1), bladder (1), lung (2), and head neck (1). Head and neck second primary was small cell undifferentiated carcinoma of the nasal cavity (diagnosed 3.5 years after RT completion and salvaged successfully). The patients in the study population had a follow-up period ranging from 3 to 123 months. Status at the last follow-up was alive without disease – 46, alive with disease – 1, alive with second primary, index disease cured – 4, dead patients – 17, dead due to other/unknown causes – 6, dead due to second primary, index disease cured – 1, and dead due to the index primary – 10 patients.
The mean OS calculated was 91.3 months. The OS at 1, 2, 3, and 4 years were 91, 84, 78.3, and 73.8%, respectively. The mean calculated DFS was 88 months. The DFS at 1, 2, 3, and 4 years were 85.2, 78.6, 72.8, and 70% respectively. The mean calculated CSS was 101.2 months, with 98.4% at 1 year, 92.4% at 2 years, 88.2% at 3 years, 83% at 4 years, and 79% at 5 years [Kaplan meier survival curves shown in [Figure 2], [Figure 3], [Figure 4].
On univariate analysis, none of the factors were found to be affecting OS. DFS was influenced by composite Stage IV versus I–III (P = 0.08) and CSS by composite stage (P = 0.08), time to start treatment after diagnosis (P = 0.02), RT break (P = 0.09), RT technique (P = 0.005).
Factors found to be significant for CSS and DFS on multivariate analysis were stage, time to start treatment after diagnosis, RT break, and RT technique.
| » Discussion|| |
The outcome of NPC has been correlated with various patient, tumor, and treatment-related factors.,,, With a median follow-up of 43 months, the OS, DFS, and CSS were 91, 85.2, and 98.4%, respectively, at 1 year; 84, 78.6, and 92.4%, respectively, at 2 years; and 78.3, 72.8, and 88.2%, respectively, at 3 years. This corresponds to the survival outcome obtained in the study by Liu et al. from Taiwan.
Excellent locoregional control was observed in our patients, with only 1 patient developing local failure, 1 patient developing nodal and systemic failure, and 10 patients failing systemically. Obviously, distant metastases were the major pattern of failure, and the most common site of distant metastasis was bone followed by the brain. The median time to recurrence was 14 months (range, 7–63 months).
On analyzing the prognostic factors that may affect the survival outcome, age (≤50; >50 years), gender, and tumor histology were not found to have a significant correlation with the survival. Grade of differentiation also did not have an impact on the outcome in our study. Only some studies have shown that females and younger patients have a better prognosis. Tumor histology has not been established as an independent prognostic factor; however, studies have shown nonkeratinizing carcinoma (both differentiated and undifferentiated subtypes) to be more radiosensitive, offering a better prognosis than the keratinizing type. Studies have shown advanced T-stage (T3, T4) is associated with poor outcomes compared to an early T-stage (T1, T2),,,, and advanced nodal stage predicts increased risk of distant metastasis with supraclavicular fossa nodes at initial presentation, thus being associated with poor outcome in terms of survival.,,, The present study did not reveal any significant correlation between T-stage and survival, but composite stage did have an impact on the outcome.
The majority of our patients belonged to Stage IVA (26) followed by Stage III (20), Stage II (10), and Stage IVB (8). Fifty percent of our patients were Stage IV who had a 4-year CSS of 70.4% compared to 96.6% in Stage I, II, and III together.
The addition of chemotherapy has shown to decrease the local, regional, and distant recurrence rates and increase the survival when compared with RT alone, with a 5-year OS rate of 70% in patients receiving CRT compared to only 59% in those with RT alone.,,
For locally advanced disease (≥T2 and/or node positive), concurrent chemoradiation therapy has become the standard of care.
A recent phase III trial from China had shown improvement in failure-free survival with neoadjuvant TPF regimen. In the present study, 8 patients received radical concurrent chemoradiation therapy alone and 55 patients received radical concurrent chemoradiation therapy with neoadjuvant and/or adjuvant chemotherapy. The impact of adding neoadjuvant chemotherapy to CRT was not significant (OS, P = 0.912; DFS, P = 0.933; CSS, P = 0.563) in the 26 patients who received neoadjuvant chemotherapy; majority (16 patients) had a high nodal tumor burden (N2/N3), whereas non-neoadjuvant group had lesser no. of N2/N3.
Other treatment-related factors that were evaluated for their correlation with the outcome were BEDT, radiation treatment break, and treatment technique.
Studies have shown that patients with T1-2 tumors have a local tumor control rate of 100% with >70 Gy, compared with 80% for those treated with 66–70 Gy., However, local control for patients with T3-4 tumors remain <55%, even with total dose of >70 Gy., Moreover, patients with interruption of RT for ≥21 days have significantly poorer local tumor control than patients without interruptions. In the present study, 59 patients received treatment with IMRT technique, whereas 9 patients with 3DCRT technique. Among the 59 patients who received IMRT, the most common dose schedule was 66 Gy in 30 fractions received by 30% followed by 70 Gy in 33 fractions received by 24% and 69 Gy in 30 fractions received by 20%. Among the 9 patients who received 3DCRT, 8 patients received a dose of 70 Gy in 35 fractions.
Because the study included patients from 2004 to 2013, there was a difference in radiation dose schedules, so BEDT was calculated for all 68 patients. The BEDT ranged from a minimum of 76.23 Gy to a maximum of 86.33 Gy. The BEDT (α/β =10) for 66 Gy/30 fractions regimen was 80.52 Gy. To assess the function of BEDT as a prognostic indicator, patients receiving a BEDT of ≥82 Gy versus <82 Gy were compared in terms of survival. With P = 0.151 for OS, 0.308 for DFS, and 0.436 for CSS, there was no statistically significant difference between the two groups.
In this study of 68 patients, 43 patients had no radiation treatment break. Of the 25 patients who had a treatment break, 12 patients had a break of ≥6 days. On analysis, it was found that 5-year CSS was 90% in patients who had no treatment break compared to 65.4% in those who had a treatment break (P = 0.076).
The impact of radiation treatment technique on locoregional control and treatment morbidity has been evaluated in a wide range of published literature., A study by Hunt et al. Compared the IMRT plans with the 2D and 3D conformal plans and found that lower normal tissue doses and improved target coverage could be achieved using IMRT that could potentially facilitate dose escalation and further improvement in locoregional control. In the present study, analysis showed a better CSS and lower incidence of late toxicities in patients treated with IMRT technique compared to those treated with 3DCRT. The improvement in CSS in the IMRT patients could not be attributed to the technique per se, as the locoregional control in both 3DCRT and IMRT was excellent with only one patient failing locally, who was successfully salvaged with brachytherapy.
In terms of radiation morbidity, percentage of patients developing acute Grade 2/3 skin reaction, radiation treatment breaks, late Grade 1/2 xerostomia were more with 3DCRT technique compared to the IMRT technique. No patient had Grade 4 radiation toxicity or treatment-related death. Hematological toxicities were also acceptable with only one patient developing Grade 4 neutropenia. Some patients developed endocrine dysfunction as a late morbidity, requiring hormone replacement therapy.
Compliance to treatment was excellent. Ninety-one percent of patients completed 75–100% of neoadjuvant/adjuvant chemotherapy and out of the 63 patients who had concurrent chemotherapy; 86% completed 66–100% of the intended concurrent chemotherapy. Tolerance to radiation was also good with only 12 patients developing an RT break of ≥6 days with most of the breaks occurring after 20 fractions of radiation treatment. On univariate analysis, “RT technique” and “duration between diagnosis and treatment” (0.30 days) were found to have a significant correlation with CSS (P = 0.005 and 0.023, respectively). On multivariate analysis, “composite stage” was found to have a significant correlation with DFS (P = 0.032) and “duration between diagnosis and treatment” was found to have a significant correlation with both DFS (0.049) and CSS (0.045).
None of the factors had a significant correlation with OS. The duration between diagnosis and treatment is a much less studied variable, which is found to be correlating both with DFS and CSS.
In our series of NPC patients treated radically with conformal RT with or without chemotherapy, the majority of patients were locally advanced, with 50% being Stage IV (IVA, IVB). As stage advances, the volume getting irradiated to a higher dose also increases, leading to increased treatment-related morbidity. Even with 50% of the patients being Stage IV (IVA, IVB), we were able to get a good locoregional control of 97% and 5 years CSS of 79% with manageable treatment-related morbidity. This could be attributed to conformal radiation therapy technique combined with a careful target delineation, planning, and treatment execution.
Limitations of the study
This being a retrospective analysis, it was subject to the limitations of the study design and sample size was small. Data regarding all the prognostic factors such as EBV DNA load were not available.
| » Conclusion|| |
In this study, with a median follow-up of 43 months, the OS, DFS, and CSS were 91, 85.2, and 98.4%, respectively, at 2 years and 78.3, 72.8, and 88.2%, respectively, at 3 years. The locoregional failure was very low (3%) and the 5-year CSS was excellent (79%) even with 50% of the patients being nonmetastatic Stage IV. The treatment-related late morbidities were acceptable. The most important prognostic factors affecting the outcome were the composite stage of the disease and duration between diagnosis and treatment initiation. With the current standard of care, a high locoregional control can be achieved even in locally advanced NPC cases with acceptable toxicity. Distant metastases remain a therapeutic challenge despite extensive use of chemotherapy. Hence, novel systemic therapies are needed in the future for improving distant control and OS of these patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]