|Year : 2016 | Volume
| Issue : 4 | Page : 493-498
Outcomes in nasopharyngeal carcinoma: Results from a nonendemic cohort
SG Laskar, L Gurram, T Gupta, A Budrukkar, V Murthy, JP Agarwal
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||21-Apr-2017|
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
INTRODUCTION: The treatment of nasopharyngeal carcinoma (NPC) has come a long way from treatment with conventional radiotherapy (RT) alone for the use of concurrent chemoradiotherapy (CCRT) and sequential chemotherapy (CT). We report the outcomes of patients treated with combined modality at a tertiary cancer center in India over a period of 10 years. MATERIALS AND METHODS: A total of 206 patients with NPC between 1994 and 2004, who completed planned treatment, were retrospectively analyzed. Demographic features, disease, and treatment-related factors were analyzed for their impact on loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS). RESULTS: Most patients had Stage III or IV (70.8%) disease. Twenty-six percent received RT alone, 37% received neoadjuvant chemotherapy (NACT) followed by RT alone, 29% received NACT + CCRT, and 8% received CCRT alone. Median RT dose was 64 Gy with 84% receiving RT doses of ≥60 Gy. At a median follow-up of 29 months, 112 (54.4%) patients were alive and disease free. Three-year DFS and OS were 64% and 82.3%, respectively. LRC at 3 years was 71.1%. Independent factors for significantly better LRC and DFS were younger age at presentation, RT dose of more than 64 Gy, and immediate response to RT. The use of CCRT in advanced nodal stages (N2–N3) resulted in significantly better LRC and DFS on multivariate analysis. CONCLUSIONS: Combined modality treatment in advanced stage NPC results in favorable outcomes. RT doses of more than 64 Gy should be considered in all patients, respecting normal tissue tolerances. The role of NACT remains debatable.
Keywords: Chemo-irradiation, nasopharyngeal carcinoma, nonendemic, prognostic factors, survival
|How to cite this article:|
Laskar S, Gurram L, Gupta T, Budrukkar A, Murthy V, Agarwal J. Outcomes in nasopharyngeal carcinoma: Results from a nonendemic cohort. Indian J Cancer 2016;53:493-8
|How to cite this URL:|
Laskar S, Gurram L, Gupta T, Budrukkar A, Murthy V, Agarwal J. Outcomes in nasopharyngeal carcinoma: Results from a nonendemic cohort. Indian J Cancer [serial online] 2016 [cited 2019 Dec 11];53:493-8. Available from: http://www.indianjcancer.com/text.asp?2016/53/4/493/204762
| » Introduction|| |
Nasopharyngeal carcinoma (NPC) is a unique entity as compared to other head and neck carcinomas in aspects related to epidemiology, etiology, presentation, and response to treatment. Although India falls in the nonendemic region for NPC, there is a high incidence in the North-Eastern regions, most commonly in the Kohima district of Nagaland, with an age-adjusted rate of 19.4% according to the Indian Council of Medical Research-National Cancer Registry Programme Registry 2002. Radiotherapy (RT) has been the backbone of treatment of NPC over many decades due to its anatomical location and inherent radiosensitivity. The results of radical RT alone have been good in early stage disease and mixed in locally advanced disease. Various studies have proven the efficacy of concurrent chemoradiotherapy (CCRT) over RT alone in the treatment of locally advanced NPC. Although loco-regional control (LRC) rates have improved with the use of CCRT, distant metastases (DMs) rates remain unchanged. Most of the published literature reports results of treatment from endemic regions where the tumor biology may be different from nonendemic areas.
In our institute, a tertiary cancer center in India, head and neck cancers comprises 25% of the annual registrations. NPC constitutes approximately 2.5% of all the head and neck malignancies. The aim of the present retrospective study was to analyze the epidemiological profile, treatment parameters, disease-related outcomes, and patterns of failure in adult patients with NPC who were treated with conventional RT over a 10-year period (1994–2004) when conformal techniques were not used. The purpose of this audit was to help us understand the behavioral patterns of the disease in our group of patients and to standardize our treatment protocol. This could also serve as a benchmark for future studies in this part of the world.
| » Materials and Methods|| |
From January 1994 to December 2004, 206 patients with histologically proven, nonmetastatic NPC treated with radical intent were included in the analysis.
All patients underwent initial evaluation which included complete physical examination, nasopharyngoscopy, and biopsy from the primary or lymph node and computerized axial tomography (CAT scan). Only 78% (162) of patients had a contrast-enhanced CT at baseline. The rest had undergone conventional X-rays for tumor assessment. Histological grading of the tumors was done according to the WHO criteria. CT scan of the abdomen/pelvis/brain and bone scan were done when symptomatically indicated. Patients were retrospectively staged as per the 1997 American Joint Committee on Cancer (AJCC) staging system.
Patients were treated with neoadjuvant chemotherapy followed by RT (NACT-RT) alone or CCRT (NACT-CCRT) and RT alone or CCRT.
The NACT was usually a cisplatin combination with ifosfamide or 5 fluorouracil in a 3 weekly regimen. Injection cisplatin 30 mg/m 2, weekly was used as the concurrent CT (CCT).
RT formed the definitive treatment for all patients. RT was delivered using either a telecobalt unit or with a 6 MV linear accelerator. Patients were immobilized using plaster of Paris casts or thermoplastic molds. The target volume of RT included the entire nasopharynx, posterior part of the nasal cavity, posterior ethmoid, sphenoid, basiocciput, base of skull, pterygoid fossa, posterior third of the maxillary sinuses, lateral and posterior pharyngeal walls, retropharyngeal lymph nodes, and cervical group of neck nodes. In patients with clinical or radiologic features suggestive of intracranial extension, the superior border was extended superiorly to include the disease extension in the RT portal adequately. Two lateral portals were the most common field arrangement. A third anterior facial field was used in patients with tumor extension into the nasal cavity or ethmoid sinuses. Tissue compensators were used in the lateral ports in majority of patients. Field reduction was done after 46 Gy to spare the spinal cord. Posteriorly involved lymph nodes were treated with electron boost (6–9 MeV). A total dose of 66–70 Gy/33–35 fractions over 6.5–7 weeks was delivered.
Response evaluation was done initially 2–3 weeks after completion of NACT and 6 weeks after completion of definitive treatment. The WHO response criteria were used to assess the response.,
Toxicity grading was based on the radiation therapy oncology group acute toxicity criteria.
Follow-up was done every 3 months for the first 2 years, 6 monthly for the next 3 years, and annually thereafter.
Survivals were calculated from the date of registration till the date of last follow-up, recurrence, or death. The persistence of disease, recurrence, and death due to disease or treatment-related events were the end points for disease-free survival (DFS), and death from any cause was considered an event for the calculation of overall survival (OS). Local control (LC), regional control (RC), and LRC were also calculated. Kaplan–Meier method was used to calculate the survival. Univariate analysis was done to identify prognostic factors. The differences between the curves were compared using the log-rank test, with a P< 0.05 taken as the significance limit.
All statistically significant prognostic variables on univariate analysis were considered in the multivariate analysis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors. Survival analysis was done using the Statistical Package for Social Sciences, version 20.0 (SPSS v20.0) Armonk, NY: IBM Corp.
| » Results|| |
Patient, tumor, and treatment characteristics
Patient, tumor, and treatment characteristics have been enumerated in [Table 1]. Median age was 43 years (range: 18–76) with a male:female ratio of 2.6:1. The most common histology seen in our set of patients was undifferentiated carcinoma (52%). Most of the patients were loco-regionally advanced at presentation (71% Stage III/IV). Ipsilateral nodal involvement was seen in 76% while contralateral nodes were involved in 35%. Most common level of nodal involvement was Level II followed by combined Level II and III in both ipsilateral and contralateral nodes.
Seventy-five (37%) patients received NACT-RT and 60 (29%) received NACT-CCRT, radical RT alone was given in 54 (26%) patients, and CCRT alone without NACT was used only in 17 (8%) patients.
Most patients were treated with parallel opposed portals with tissue compensators followed by off-cord bilateral portals. The median RT dose was 66 Gy (range: 50–80 Gy). Eighty-four percent (173) completed the planned course of RT. Treatment was interrupted in 16% of patients either due to severe acute reactions or poor compliance. The median duration of RT was 51 days (range: 29–132). There were no deaths on treatment.
NACT was given in 135 patients (65.5%). Cisplatin was used in 93% patients with a median dose of 120 mg/cycle in the NACT setting. Forty-two percent received a 5-day course, while 31% received a 2-day course. Ifosfamide was given in addition to cisplatin in about 60% patients with a median dose of 10 g/cycle. 2-mercaptoethane sulfonate Na was used along with ifosfamide. The overall response rate to NACT was 75%.
Thirty-seven percent patients received CCRT. The median number of CCT cycles was 6 (range: 1–8). The median cumulative dose of cisplatin during the CCRT was 300 mg (range: 40–450).
Seventeen patients (8.3%) were lost to follow-up immediately post-RT. Complete response (CR) after completion of all treatment was seen in 151 (73.3%) patients while 23 (11%) patients had a partial response. Poor response or progressive disease was seen in 15 patients (7%).
Overall survival, disease-free survival, and loco-regional control
The median follow-up of all patients was 29 months (interquartile range: 12–100). Seventy-three patients (35%) had a follow-up of more than 5 years.
The 3-year OS for the whole group was 82.3%. The 3-year LC, RC, LRC [Figure 1], DFS [Figure 2], and DM free survival (DMFS) rates were 64%, 77%, 78.9%, 71.1%, and 84.9%, respectively. Persistent disease at primary or node was seen in about 12%. One patient developed a second primary at lower alveolus. No significant difference in DFS was seen in patients who received NACT compared to CCRT [Figure 3].
|Figure 1: Kaplan–Meier curve depicting loco-regional control rate in the whole group|
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|Figure 2: Kaplan–Meier curve depicting disease-free survival in the whole group|
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|Figure 3: Kaplan–Meier curve depicting disease-free survival in patients stratified by neoadjuvant chemotherapy versus radiotherapy/concurrent chemoradiotherapy|
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The various prognostic factors studied on univariate analysis are shown in [Table 2].
|Table 2: Prognostic factors of disease-free survival on univariate analysis group-wise|
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A separate analysis was carried out to compare the outcomes in patients treated prior to 1999 versus patients treated thereafter till 2004. There was a trend toward improvement in 3-year LRC (P = 0.07) in patients treated after from 1999 onwards; however, there was no difference in DFS.
On multivariate analysis, early nodal stage (N0–N1), patients younger than 35 years and CR to RT had a significantly better DFS [Table 3]. In addition, the use of CCT showed a trend toward significance (P = 0.08) with respect to DFS.
|Table 3: Prognostic factors of loco-regional control and disease-free survival on multivariate analysis group-wise|
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The 3-year DMFS rate was 84.9%. The most common site of distant failure was skeletal (bones) followed by liver. The median time to development of DM was 12 months and the median OS of these patients was 19 months. The nodal stage had a significant impact on DMFS with N0–N1 patients having a DMFS of 90.6% versus 75.4% in N2–N3 patients (P = 0.02).
American Joint Committee on Cancer Stage III–IV
In advanced AJCC stage groups (146 patients), age, histology, early nodal subgroup, RT dose, and RT response affected LRC and DFS on univariate analysis as shown in [Table 2] and [Table 3]. The use of CCRT improved LRC rates significantly. On multivariate analysis, RT dose of >64 Gy, younger age, and CR to RT had a significant impact on LRC, whereas for DFS, in addition to the above factors, early nodal disease (N0–N1) had better DFS.
In advanced T-stage tumors (105 patients), RT dose of >64 Gy, CR to RT improved LRC, and DFS significantly on univariate analysis [Table 2]. On multivariate analysis in this subgroup, age <35 years, addition of CT in general, and CR to RT were significant predictors for improved LRC and CR to RT was the single most important factor for DFS [Table 3]. The prognostic factors analyzed in advanced nodal stage (N2–N3) are shown in [Table 2] and [Table 3]. On multivariate analysis, age <35 years, addition of CT in general, and CR to RT response significantly improved 3-year LRC and DFS [Table 4].
|Table 4: Patterns of failure. Seventeen patients were lost to follow-up immediately after primary therapy|
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Patterns of failure and management of recurrent disease
The patterns of failure with disease status at last follow-up are depicted in [Table 4].
During CT, the major adverse effect documented was Grade 1 and 2 neutropenia (19%). None of the patients had febrile neutropenia or significantly deranged liver or renal functions.
The acute effects during RT were primarily associated with the skin and mucosa. Sixty-two percent had Grade 2 skin toxicity and 61% had Grade 2 mucositis during or at RT completion. In 16 (7.7%) patients, the treatment was interrupted because of acute treatment toxicities out of whom eight received CCRT and eight received radiation alone. Six (2.9%) of these patients required hospitalization for supportive care, in five (2.4%) patients the total dose had to be decreased, while five others completed planned treatment with a break.
Two patients were presumed to be dead due to treatment-related toxicity as they were lost to follow-up immediately after RT. On further enquiry, it was found that they died within a few days of treatment completion.
| » Discussion|| |
We report the results of nonmetastatic NPC patients treated with RT, with or without CT, during 1994–2004, when conventional RT was the standard practice. This is the first report from our part of the world, which is essentially considered a nonendemic region for NPC. The prognostic factors affecting the outcomes have also been analyzed. In our series, it was observed that younger age (<35 years) patients had significantly better LRC rates and DFS. Shigematsu et al. in their report of NPC patients treated with radical RT alone showed that age is an important prognostic factor for survival. Similarly, Cheng et al. also showed that age is a significant factor when treated with chemo-RT.
Histology in our group of patients was also an important prognostic factor for LRC and DFS in advanced stages with undifferentiated type having better outcomes. The literature from the nonendemic areas has shown that histology can be an important predetermined factor for outcomes. Most of the tumors have epidermoid histology in the Western population, which have shown poorer outcomes as compared to undifferentiated type. However, no conclusive results have been obtained as yet.,, RT dose is an important factor to achieve optimal LRC rates which has been demonstrated in various studies. The older studies by Marks et al. and Vikram et al. had shown the importance of higher doses (>66 Gy) for achieving optimal LC., This is pertinent especially in conventional RT due to higher inhomogeneity in the delivery of doses and the chances of underdosing in the peripheral areas of the fields. The dose of >64 Gy had a favorable impact on survival in our group. Immediate response to RT is a significant predictor of long-term outcomes, similarly in our series, patients who had CR following RT had significantly better survival rates. RT dose escalation, in addition to higher xerostomia rates, also carries a high risk of other late sequelae such as trismus, higher auditory impairment, temporal lobe necrosis, and endocrine abnormalities. This is very pertinent especially when RT is delivered with conventional two-dimensional planning. Unfortunately, the retrospective nature of our study limits information on late toxicity.
The nodal stage has been an important factor predicting loco-regional recurrence rates as well as DM., This was found to be true even in our series in patients with N0–N1 disease having improved outcomes as shown in [Figure 4].
|Figure 4: Kaplan–Meier curve depicting disease-free survival in patients stratified by N0–N1 versus N2–N3 stage|
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RT has been the main modality of treatment in early NPC. However, very few patients present with early stage disease at our center. In our group, only 22 patients presented with T1–T2, N0 disease of which only seven patients received RT alone. Radical radiation alone is seldom used in the present scenario for the treatment of even early stage NPC. Possible indications would be a very select group of Stage I patients where old age or the presence of medical comorbidities preclude the use of CT. Since this is a retrospective audit, we had 54 patients with variable stages who received RT alone, for various reasons such as poor performance scores, presence of medical comorbidities, or very early stage disease, majority treated before the year 2000. The 3-year DFS of this subgroup was 54.6%. However, the results with RT alone in locally advanced disease have been suboptimal.,
Various studies have shown the benefit of CCRT over RT alone in terms of LC and OS. Langendijk et al. in a meta-analysis of 2450 patients in 10 randomized clinical studies ascertained that concomitant CT in addition to radiation is an effective way to improve the OS in NPC. The individual patient data meta-analysis by Baujat et al. showed a significant survival benefit in patients treated with CCRT. The meta-analyses and many other randomized studies have clearly established the role of CCRT in locally advanced NPC patients. The addition of CCT to radiation either with or without NACT improved survival significantly in patients with either advanced T (T3/T4) or advanced N stage (N2/N3). This can be explained by the fact that advanced T and/or N stages are at a higher risk for micrometastases and the benefit of CT is more pronounced in these stages. Sun et al. compared the results of advanced N stage treated with various sequencing of CT. The 5-year OS rate was 73%. There were no significant differences among the various schedules though NACT-CCRT had higher DMFS rates. The higher survival rates in this study may be due to the intensity-modulated RT (IMRT) used. Kong et al. reported that NACT followed by CCRT was well tolerated with Grade 3/4 hematological toxicities observed in 55% of the patients. NACT was well tolerated and significant response obtained prior to initiation of RT in our patients. The meta-analysis by OuYang et al. evaluated the efficacies of NACT and adjuvant CT, it was observed that NACT showed a survival gain of 5% after 3 years and a reduction in DM which was not seen in the adjuvant setting.
NACT is an effective option in locally advanced NPC patients with the potential to reduce DM. Most of these patients are treatment naïve and tolerate CT better with 20–25% patients requiring dose reduction in the third cycle. NACT also reduces the tumor burden which helps in RT planning and optimal margins can be given with appropriate doses with adequate sparing of normal tissues. The need for repeat planning is reduced. About 75% of patients achieved a clinically significant response in our series with nearly 40% having more than 75% regression in disease bulk.
The policy of using NACT followed by CCRT had started more like an adaptation to the logistics-driven setting at our center with the huge patient load leading to long waiting lists for starting treatment such that it is always not possible to initiate CCRT at the earliest. In such a scenario, it would be very important to determine the detrimental effect of late start of concurrent therapy vis-à -vis the advantages attained with immediate initiation of NACT and subsequent consolidation with CCRT. Theoretically, a benefit in LRC and survival is expected with NACT, though the same magnitude of benefit may not be realized in clinical practice. Of the five randomized trials comparing NACT followed by RT and RT alone, the outcome has been mixed with three showing a positive result and two showing a negative result. The International Nasopharynx Cancer Study Group improved response and reduced failure, without improvement in survival, with NACT followed by RT when compared with RT alone. Our results are similar to the above studies with NACT not having a significant impact on LRC rates or DFS. At the same time, there was no increase in disease-related events or toxicity in the patients receiving NACT.
The prognostic factors such as age, stage, RT dose, and the addition of CT in advanced stages have shown significance in a number of studies and have become important criteria for assessment of outcomes, which has also been reflected in our study.
The main limitation of the study is its retrospective nature and associated shortcomings. The incidence of late sequelae is underestimated and there were a higher percentage of patients who were lost to follow-up.
Our results are slightly inferior as compared to the reported outcomes in endemic regions treated with conventional RT with the addition of CT. Wee et al. reported 3-year DFS and OS of 72% and 80%, respectively. The multicentric trial by Ohno et al. reported 3-year LRC and OS rates of 89% and 66%, respectively. This may be explained by the higher number of patients in advanced stages and larger proportion of patients with differentiated carcinoma.
| » Conclusions|| |
This retrospective analysis has reported outcomes in NPC patients in nonendemic region treated with conventional RT techniques with or without CT. The results with conventional RT have been in the acceptable range with mild to moderate toxicities. The reported results are from a period when IMRT was not in vogue. We have started using IMRT in NPC at our institute since 2004. The use of IMRT has resulted in conformity, superior dose delivery, and better organ at risk sparing. The use of CT, concurrent with RT, especially in advanced stage disease has been formalized with the results from prospective trials.,
Financial support and sponsorship
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]
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