Clinical Study on Simultaneous Modulated Accelerated Radiotherapy and Concurrent Chemotherapy for Locally Advanced Nasopharyngeal Carcinoma

Discussion

One pronounced advantage of the IMRT technique is that the high dose isodose lines conform with the target volumes and the doses in 1 volume are evenly distributed. This is especially important for nasopharyngeal carcinoma because of the complicated anatomical structures surrounding the tumor^[3-6].

The other advantage of the IMRT is that the beam’s intensity can be modulated. Therefore, it is possible to deliver simultaneously integrated boost radiotherapy of different fractional doses to the target tumor, subclinical area, and to the area that needs to be preventively irradiated in the neck, and elevates biologic equivalent doses in the target volumes. So it can be classified as one type of accelerated radiotherapy. Reduction of the treatment time may result in some benefits, such as repressing the proliferation of tumor cells, enhancing therapeutic efficacy, and sparing normal tissues^[7]. The SMARTIMRT technique was initially introduced and utilized in head and neck tumors by Butler^[8]. Trials demonstrated that this technique could elevate the local control rates, without causing severe toxicities. Besides, the symptom of xerostomia could be significantly relieved 6 months after completion of the radiotherapy. Chen et al.^[9] found that SMARTIMRT was superior to the conventionally fractionated IMRT in increasing doses of the tumor volume and sparing adjacent normal organs, especially the parotid glands.

Many studies have proven that patients with locally advanced nasopharyngeal carcinoma, who were applied chemoradiotherapy concurrently, could attain an improved local control rate and survival rate than the patients who were applied radiotherapy alone^[10]. The possibility of metastasis could be reduced as well. These results were based upon the following theories: i) Cytotoxicities of the chemotherapy agents decrease the tumor burden, and ameliorate the blood supply and hypoxia of tumor. ii) Synchronization of tumor cells is made by chemotherapeutic agents and tumor cells are sensitized to radiation. iii) Chemotherapy could interfere with, or inhibit the tumor cells that are sublethal, or potentially lethal damaged after radiation, and could produce synergy with the radiotherapy. iv) Chemotherapy has the potential to eliminate the subclinical metastasis. Huncharek et al.^[11] collected 6 randomized trials, including 1,528 patients treated with chemotherapy/radiotherapy, concurrent chemoradiation or radiotherapy/adjuvant chemotherapy. The results revealed that chemoradiotherapy could increase the 2-year, 3-year, and 4-year survival rates by 20%, 19% and 21%, respectively, and increase the 2-year, 3-year, and 4-year disease free survival rates by 37%, 40% and 34%, respectively (P < 0.05), compared with the radiotherapy alone. One comprehensive analysis presented in the 2004 ASCO meeting, including 78 randomized trials which enrolled 9,279 patients together^[12], revealed that i) the concurrent chemoradiotherapy could increase the 5-year overall survival; ii) the concurrent chemoradiation in combination with adjuvant chemotherapy could increase the 5-year disease free and overall survival. Of these 2 conclusions, efficacy of the cisplastinbased concurrent chemotherapy was the most significant. The IGS (Intergroup study 0099) randomized control study initially confirmed^[13] that 3 cycles of concurrent chemoradiotherapy with high dose cisplatin (100 mg/m², in the 1^st day every 21 days) followed by adjuvant chemotherapy containing cisplatin plus 5-Fu could increase the 3-year survival rates by 31%. However, only 55% of the patients could complete the adjuvant chemotherapy as planned, due to severe toxicities. Baujat et al.^[14] undertook one metaanalysis, consisting of 8 prospective trials which enrolled together 1,753 patients with locally advanced nasopharyngeal carcinoma. It was concluded that the chemoradiotherapy could increase the 5year overall survival rates by 6% and disease free survival rates by 10%, in comparison with single radiotherapy. Similar conclusions were also made by Chen et al.^[15] and Peng et al.^[16]

The concurrent chemoradiotherapy could aggravate the acute side effects caused by radiation, especially the acute inflammation of mucosa. The principle advantages of SMARTIMRT is that there is less damage to surrounding normal organs and tissues, and less toxicities which result in an improved treatment. It was very critical to select safe and effective chemotherapy agents in order to avoid severe mucositis caused by concurrent chemoradiation. Many trials have proven that the sensitization effect of cisplatin was observed to be less in patients with nasopharyngeal carcinoma, without overlapping toxicity with radiation. Consequently, cisplatin could improve the efficacy, without causing serious side effects. Our study found that the acute toxicities in the PF group increased significantly in comparison with cisplatin alone, but no difference could be observed in terms of long-term toxicities, survival rates, and with local and regional control rates. Lee et al.^[17] applied SMARTIMRT for 20 patients with nasopharyngeal carcinoma, among which 18 patients underwent concurrent chemoradiotherapy with single agent of cisplatin. All the patients completed the treatment, except 1 interrupted for 2 weeks due to severe pharyngeal reaction and malnutrition. The 2-year regional control rate reached as high as 88%, and the metastasis free survival rate 90%. The grade 3 acute pharyngeal reaction and mucositis were 45% and 25%, respectively, without grade 3 or 4 salivary glands reaction. In the longer period of follow up, the symptom of xerostomia was found to gradually decline. Koom et al.^[18] reported that the 3year overall survival rate, local control rate, regional control rates and metastasis free survival rates were 96%, 93%, 87% and 88%, respectively. The 3-year survival and local control rates in both single cisplatin and PF concurrent chemoradiotherapy groups were similar. The incidence of acute pharyngeal and mucosa reaction in cisplatin group was 34% and 47%, respectively, while in the PF group, both incidence of the 2 reactions were 100%. The differences in the incidence of the reactions between the 2 groups were statistically significant. But no grade 4 acute toxicity occurred in both groups. These indicated that combination of single cisplatin with radiotherapy could be easily tolerated by the patients. In our trial, small amount of cisplatin was utilized, which resulted in less acute toxicity and increased tolerance of the patients to the toxicity compared with PF plus CF regimens. The 3-year overall survival rate was 91.3%, slightly lower than that reported in the literature, perhaps due to more cases with locally advanced disease.

At present, consensus has been reached in terms of concurrent chemo-radiotherapy as the standard treatment for locally advanced nasopharyngeal carcinoma. But few clinical trials with a large number of subjects has been undertaken with respect to concurrent combination of chemotherapy with SMART. Therefore, more data are required to determine its long-term efficacy and toxicity. Further investigation is needed in selecting effective and safe chemotherapeutic agents.