|Year : 2009 | Volume
| Issue : 2 | Page : 102-106
Results of combined modality treatment for nasopharyngeal cancer
Ramachandran Venkitaraman1, S Ganapathy Ramanan2, A Vasanthan2, Tenali Gnana Sagar2
1 Division of Clinical Oncology, Ipswich Hospital, United Kingdom
2 Division of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai - 400 036, India
|Date of Web Publication||16-Jun-2009|
Consultant Clinical Oncologist, Ipswich Hospital NHS
Source of Support: None, Conflict of Interest: None
Context: Radiotherapy is the cornerstone of treatment in nasopharyngeal cancer (NPC); the addition of chemotherapy has shown improved results.
Aims: To compare the results of concurrent chemoradiation with that of radiotherapy alone in NPC.
Materials and Methods: One hundred and ninety consecutive NPC patients, without distant metastasis, who reported to the institute from January 1992 to December 2001, received external-beam radiation to 66 Gy in 33 fractions. Seventy-five of these patients received concurrent chemotherapy with cisplatin and 5-fluorouracil (5-FU) for four cycles. We compared the results of treatment in these two groups.
Results: The 5-year disease-free survival rates were 40% and 60%, respectively, for patients who had radiotherapy alone and those who had chemoradiation (P = 0.002), while the median survival was 45 months and 60 months, respectively (P = 0.0028).
Conclusion: A significant improvement in local control and survival was observed by the addition of concurrent chemotherapy with cisplatin and 5-FU to radical radiation in this nonrandomized study on patients with NPC.
Keywords: Chemotherapy, nasopharyngeal cancer, radiotherapy
|How to cite this article:|
Venkitaraman R, Ramanan S G, Vasanthan A, Sagar TG. Results of combined modality treatment for nasopharyngeal cancer. J Can Res Ther 2009;5:102-6
| > Introduction|| |
Nasopharyngeal carcinoma (NPC) is unique among head and neck malignancies in its exquisite sensitivity to radiotherapy and chemotherapy and good survival characteristics, even in advanced stages of presentation. ,,,
Radiotherapy has been the cornerstone of treatment of carcinoma nasopharynx. Chemotherapy, as neoadjuvant, adjuvant or concomitant has been added to the treatment regimen in NPC in randomized and nonrandomized studies in an attempt to improve the response. ,,,, We conducted a study to compare the results of radiotherapy and concurrent chemoradiotherapy in patients with nonmetastatic carcinoma of the nasopharynx.
| > Materials and Methods|| |
The study population consisted of 190 consecutive patients who reported to the Cancer Institute, Adyar, Chennai, from January 1992 to December 2001. All had histology-proven carcinoma nasopharynx (TNM 1997 stages I to IVB). They were prospectively included in the Cancer Institute protocol after they had given informed consent. The treatment protocol was cleared by the ethics committee of the institution. Exclusion criteria were the presence of distant metastasis, World Health Organization (WHO) performance status ≥ 2, and impaired renal or hepatic function.
All patients underwent a clinical examination, which included a nasopharyngoscopy and biopsy, and evaluation of the cervical lymph nodes by fine needle aspiration cytology or biopsy if required. Immunohistochemical studies on the biopsy specimens were conducted whenever necessary to distinguish from lymphoma from other round-cell tumors. Histologic subtyping was done according to the WHO system, which classifies these tumors as keratinizing or nonkeratinizing squamous cell carcinoma (type I or II) and undifferentiated carcinoma (type III). Radiograph of the thorax, ultrasonographic evaluation of the abdomen, and CT scan of the paranasal sinuses was mandatory to assess the parapharyngeal and intracranial extension and to plan radiotherapy. Tc-99-MDP bone scan and radiography of the suspicious sites were also performed, and patients with bone metastasis at presentation were excluded. Staging of the patients was done utilizing the AJCC 1997 system for staging classification of carcinoma nasopharynx.
The assignment to treatments, either radiotherapy or chemoradiotherapy was nonrandomized and depended on the era of treatment, preference of the treating physician, and patient choice. Chemotherapy consisted of an infusion of cisplatin 80 mg/m 2 on the first day and 5-fluorouracil (5-FU) 350 mg/m 2 bolus for 3 days. Radiation was started on the fourth day of the first cycle of chemotherapy. The same chemotherapy regimen was continued as concurrent and adjuvant for four cycles, repeated every 3 weeks. Delay in chemotherapy or radiotherapy was allowed for any grade III or IV hematologic or gastrointestinal morbidity and any other grade IV morbidities. Reduction of the chemotherapeutic drug dose or radiotherapy dose was not allowed.
All patients received external-beam radiation to 66 Gy in 2-Gy fractions five times a week over 7 weeks, with 4-6 megavoltage (MV) photons to the nasopharynx, parapharyngeal areas, and base of skull. Any intracranial extension was irradiated with 1cm margins superiorly, while any nasal extension was treated by a three-field technique, including an anterior field. An intraluminal brachytherapy boost of 8-10 Gy was given using Iridium-192 in patients with locally advanced tumor or if residual lesion was suspected clinically at the end of external radiation. None of the patients in the study received three-dimensional conformal radiotherapy. All patients received 45 Gy to the entire cervical nodal areas by 4 MV photons, followed by 10 Gy by electrons, sparing the spinal cord. Bulky or residual cervical nodes received a boost of 5-10 Gy by electrons of appropriate energy. The radiation dose and technique were the same in both groups of patients.
Evaluation of the patients after completion of chemotherapy was by clinical examination, nasopharyngoscopy and biopsy if required, and biopsy of the residual cervical node, with modified radical neck dissection if indicated. Follow-up included 3-monthly visits to the hospital during which the patient underwent a clinical examination, including nasopharyngoscopy. Other investigations were indicated only if the patient became symptomatic. The prognostic factors assessed were age < 15 years, T status, N status, AJCC stage, histology, and addition of concurrent chemotherapy. Survival data was analyzed by the Kaplan-Meier method and comparison of prognostic factors by Cox's proportional hazards model, with a P < 0.05 considered significant.
| > Results|| |
A total of 190 patients were enrolled in the study [Table 1]. The median age at presentation was 31 years (range 7-69 years). Twenty-seven patients (14%) were in the pediatric age-group. The male/female ratio was 2.5:1. The commonest presentation was as a cervical lymph node in 65% of cases, followed by epistaxis in 23%. Sixty-six percent of the study subjects were not users of tobacco products. There were four patients with stage I disease, 23 with stage II disease, 87 with stage III disease, and 76 with stage IV disease [Table 2]. In our patient population, 73% had poorly differentiated or undifferentiated carcinomas (i.e., WHO type 3). One hundred and fifteen patients received only radical radiotherapy which consisted of 66 Gy or more to the primary and 55 Gy or more to the cervical nodal areas. The other 75 patients received, in addition, concurrent chemotherapy with a cisplatin-containing regime for four cycles. The median follow-up period was 46 months (range 8-116) and the 'lost to follow-up' rate was 14%.
Eighty percent of the 190 patients had a complete response at the end of treatment [Figure 1] and [Figure 2]. Fifty-eight percent of the patients who received radiotherapy alone relapsed, compared to 28% of patients who also received concurrent chemoradiation.
A predictor found to have prognostic significance was T4 status, with the 5-year disease-free survival (DFS) in these patients being 41% as compared to 58% in the patients with T1-3 status ( P value = 0.03) (hazard ratio 2.35; 95% CI: 1.2 to 2.8) [Table 3]. Poorly differentiated carcinoma (WHO type 3) fared significantly better than carcinoma with squamous histology (WHO type 1 and 2), with 5-year DFS of 56% and 44%, respectively ( P = 0.01) (HR 0.78; 95% CI: 0.67 to 0.98).
Patients who received chemotherapy had significantly improved survival compared to patients who had radiotherapy alone ( P = 0.001) (HR 0.33; 95% CI: 0.3 to 0.66). The addition of concurrent chemotherapy, in the form of cisplatin and 5-FU, was found to provide significant advantage, both for DFS and overall survival. The 5-year DFS was 40% in patients who received radiotherapy and it was 60% in those who also received concurrent chemotherapy (log rank P = 0.002); similarly, median survival was 45 months in patients who received radiotherapy and 60 months in patients who received concurrent chemotherapy (log rank P = 0.0028). Both locoregional and distant recurrences were fewer in the patients who received chemoradiation than in the patients who received only radiation.
Morbidities were significantly more in patients who had concurrent chemotherapy, especially grade 3-4 hematologic and mucosal toxicities; this necessitated frequent treatment interruptions in 42 (56%) patients. None of the patients who received radiation alone had significant hematologic morbidity and most patients could complete their treatment as scheduled within 7-8 weeks. Delay in chemotherapy was not found to adversely affect DFS.
| > Discussion|| |
In our series of patients, we found that concurrent chemoradiation significantly improves DFS and overall survival over that provided by radiotherapy alone. Radiotherapy is the standard treatment for all NPC and, though effective in the early stages, it may be inadequate in the higher stages of disease, giving 5-year survival rates of only 10-40% for stage III and 0-30% for stage IV disease. , Increase in T status has been correlated to increased risk of local recurrence, while increase in N status has been correlated with high risk of distant metastasis. In our series too, patients with T4 disease were found to fare poorly, suggesting the need for more intensive treatment in this group of patients. Higher doses of radiation have been shown to produce better local control, but they may not produce any survival advantage as distant failures are the commonest cause of death, especially in higher stages of disease and in the presence of undifferentiated pathology. Locoregional relapses have been shown to herald distant metastasis, with 50% occurring within 5 years. 
Most of the relapses after treatment occur within the first 2 years and more than 50% relapse at distant sites. The fairly short time to the development of distant metastasis might indicate the presence of occult systemic disease at presentation. Initial systemic therapy must therefore be effective.
Combination chemotherapy may produce response rates of 60-70% in recurrent and metastatic disease, but does not provide long-term cures; the combination of cisplatin and 5-FU may be considered the standard regimen for patients with NPC., Induction chemotherapy has been tried in three randomized studies, with excellent response rates, but no significant survival advantage has been documented. In the INCSG study-where three cycles of chemotherapy with bleomycin, epirubicin, and cisplatin, followed by radical radiation was used-the DFS was found to be improved. The study from the Sun Yat Sen University, where two cycles of cisplatin, bleomycin, and 5-FU were used, also produced improvement in local control rates, but no survival advantage was noted. The benefit of induction chemotherapy may lie in bulk reduction, increasing the probability of the gross residual disease receiving the full dose of radiation and allowing a reduction in the volume of normal tissue irradiated, thereby increasing the control rates and decreasing the late morbidities.
Concomitant use of radiation and chemotherapy can exploit the independent complementary action of radiation locally and chemotherapy distally.
Chemotherapeutic drugs, especially cisplatin, 5-FU, and bleomycin, have been shown to have radiosensitising properties and may cause sufficient increase the locoregional control rates to produce a survival advantage when used concurrently with radiotherapy. The intergroup 0099 study included 185 patients belonging to nonendemic regions, with predominantly WHO type I or II histology; about 39% of patients had undifferentiated carcinoma. Treatment, consisting of cisplatin 100 mg/m 2 , was given for three cycles concurrently with a radiation dose of 70 Gy; this was followed by adjuvant chemotherapy with cisplatin 80 mg/m 2 on day 1 and 5-FU 1 g/m 2 /day infusion for 4 days; three cycles of this regimen were given after radiation. When compared to radiation alone, a significant reduction in both locoregional recurrences and distant failures were seen. Fifty-five percent of patients received all three planned cycles, while 33% did not receive any adjuvant chemotherapy due to the toxicity. 
The Princess Margaret study involved 350 assessable patients. Patients in the combined-modality arm received 40 mg/m 2 of cisplatin weekly, given for 8 cycles during radiotherapy. A significant improvement in DFS favoring chemoradiation was detected in patients with advanced stages of disease, mainly due to a reduction in distant metastasis.  The aim of concomitant treatment should be to incorporate both modalities optimally without producing significant morbidities and without compromising the dose intensity of either modality. In a meta-analysis of chemoradiotherapy trials in the nasopharynx, the highest benefit was for concurrent chemotherapy, with a pooled HR of 0.48 (95% CI: 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. 
Adjuvant chemotherapy, though it may theoretically decrease the rates of distant metastasis, has not by itself been shown to produce any survival advantage in a randomized trial. The study by Rossi et al. , used postradiation vincristine, cyclophosphamide, and doxorubicin without any advantage. This may probably be due to the noninclusion of cisplatin, the most active agent. 
Though the acute treatment-related morbidities like mucositis and cytopenia are more with the addition of chemotherapy, late morbidities, except ototoxicity, has not been found to be significantly increased in any series.
Undifferentiated NPC or WHO type III was the major pathologic subtype in our patients, which is similar to the pattern seen in the far-eastern endemic regions. Another notable aspect of our study was the high proportion of children and adolescents, which is not a feature seen in either the endemic eastern or the non-endemic western series. Among the head and neck cancers, undifferentiated NPC has the highest rates of metastatic disease at presentation (5-11%), which necessitates the use of effective systemic treatment. In our series, undifferentiated carcinoma was found to fare better than the squamous cell variants.
The advantage of our protocol was that the chemotherapy schedule acted as neoadjuvant, concurrent, and as adjuvant along with radiation and thus may have provided the benefits of all three approaches: induction chemotherapy producing good response, with a downsizing of the disease; concurrent chemotherapy producing a radiosensitising effect, leading to better local control; and the adjuvant chemotherapy effecting a decrease in rates of distant metastasis.
Both radiotherapy and concurrent chemoradiation produced similar complete responses rates; however, in patients who received concurrent chemoradiation, the local recurrences, regional nodal relapses, and distant metastasis were significantly reduced. The survival advantage seen with the concurrent use of chemotherapy may be due to a reduction of all three types of failures. NPC with T4 status was found to fare significantly poorly, which may be due to the relatively low dose of radiation given. N3 status had no significant effect. NPC with squamous histology (WHO types I and II) had poorer DFS and overall survival than NPC with poorly differentiated histology, and most of these relapses were locoregional. There was significant morbidity in patients who had concurrent chemoradiation, with 56% patients unable to complete the treatment on schedule. All patients completed radiation treatment, though chemotherapy was delayed due to mucositis and neutropenia in 80% of patients. The benefit in DFS and overall survival was evident in those receiving concurrent chemoradiation in spite of the fact that this group had more patients with T4, N3, and stage IV disease than the group that had radiotherapy alone [Table 2] and [Table 3].
The major drawback of our study is the nonrandomized assignment of treatment and the lack of prospective and systematic recording of late morbidity data.
| > Conclusion|| |
Carcinoma nasopharynx, treated with radiation and chemotherapy, shows good survival rates, even when the disease is at an advanced stage at presentation. A statistically significant improvement in local control and survival is observed by the addition of concurrent chemotherapy with cisplatin and 5-FU to radical radiation in nonmetastatic carcinoma nasopharynx; this should be regarded as standard therapy.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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