Abstract
OBJECTIVE To evaluate the clinical efficacy and toxicities of simultaneous modulated accelerated radiotherapy (SMART) and concurrent chemotherapy for locally advanced nasopharyngeal carcinoma.
METHODS Eightyseven patients with nasopharyngeal carcinoma received SMART from April 2002 to September 2006. According to the UICC staging system, 30 patients were diagnosed as stage IIb, 42 patients stage III, 13 patients stage IVa and 2 patients stage IVb. The intensitymodulated radiotherapy was delivered with the “step and shoot” SMART technique with the prescribed dose of 66-76 Gy (2.2-2.4 Gy/day) to the gross tumor volume (GTV) and positive neck lymph nodes (GTVLN), with 60 Gy (2.0 Gy/day) to the highrisk clinical target volume (CTV1), encompassing the area around the nasopharynx and the upper neck, and with 54 Gy (1.8 Gy/day) to the lowrisk clinical target volume (CTV2), including the lower neck and supraclavicular area. Among all the patients, 31 received 2 cycles of SMART concurrently with 5 fluorouracil (5-Fu) and cisplatin (the FP group) and 56 received 2 cycles of concurrent cisplatin. All the patients received 3 to 4 cycles of adjuvant combination chemotherapy of cisplatin and 5fluorouracil starting from the 1st month aft er completion of SMART.
RESULTS With a median follow up of 59 months (ranging from 19 to 85 months), the 1, 2 and 3year overall survival rates were 100%, 94.6% and 91.3% respectively. Acute mucositis and pharyngitis were more frequently observed in the FP group than in the cisplatin group.
CONCLUSION SMART technique provides an excellent opportunity to spare normal tissue and is probably more biologically effective. Combination of single cisplatin was more tolerable.
keywords
- simultaneous modulated accelerated radiotherapy (SMART)
- intensitymodulated radiotherapy
- nasopharyngeal carcinoma
- concurrent chemoradiotherapy
Introduction
Intensity modulated radiotherapy (IMRT) is a novel technique, which can expose highly conformal dose distribution to the tumor volume without damaging the adjacent normal tissues. Because IMRT can control the beam intensity in the radiation fields, simultaneous modulated accelerated radiot herapy (SMART) has become available and demonstrated advantages in reducing treatment time and increasing radiobiological effects. The 5-year survival rate of the locally advanced nasopharyngeal carcinoma is only approximately 35%, mainly because of metastasis and local relapse[1,2]. It is reported that concurrent chemoradiotherapy can elevate the clinical efficacy, but conventional or 3-dimension conformal radiotherapy and chemotherapy simultaneously applied is not well tolerated because of the severe toxicities they may cause. Our hospital has applied the SMART technique in combination with chemotherapy concurrently to treat locally advanced nasopharyngeal carcinoma since April 2000 and has achieved good results.
Materials and Methods
General data
From April 2000 to September 2006, 87 patients with nasopharyngeal carcinoma who were never treated before were enrolled in the study. Among the patients, 65 were male and 22 female in age ranging from 12 to 69 years (median age of 47 years). Fifty-three patients were diagnosed as lowdifferentiated squamous carcimona while the remaining 34 patients as undifferentiated carcinoma after pathological examination. All the patients were examined by chest X-ray, cervical and abdominal ultrasound, nasopharyngeal and cervical CT/MRI, cranial MRI and bone scintigraphy prior to treatment. According to the UICC staging system, 30 patients were classified as stage IIb, 42 in stage III, 13 in stage IVa and 2 in stage IVb (Table 1). Patients with stage III and IV accounted for 66%.
T and N staging.
Treatments
Before taking computed tomography (CT) images, all the patients were immobilized in a supine position with the head fixed by a head support and a thermoplastic mask. The reference points were set by 3-dimension laser and then marked by metal markers. Volumetric CT images were taken from the scalp to the region 3 cm below the inferior margin of the clavicle, with the CT slice thickness of 3 mm to 4.5 mm. Targets were defined according to the ICRU report 50 and 62.
The GTVnx was defined as the nasopharyngeal carcinoma volume visible in the enhanced CT and MRI. The GTVnd was the target volume of metastatic cervical lymph nodes, defined as nodes’ shortaxis diameter larger than 1 cm in the enhanced CT scan with central necrosis and uneven enhancement, or fused multiple lymph nodes. The clinical tumor volume (CTV) 1 was defined as the most vulnerable region infiltrated by tumor and the upper and middle cervical lymph nodes region. The planning target volume (PTV) 1 was formed by the CTV1 plus 3 mm margins. The organs at risk, such as brain stem and spinal cord, should have added margins of 1 to 2mm. The CTV2 was defined as the lower cervical and supraclavicular lymph nodes region. The PTV2 was formed by the CTV2 plus 3 mm margins. The normal organs, including parotid glands, brain stem, spinal cord, optic chiasm, optic nerves, eyes, lens and temporomandibular joints, etc., were delineated so as to avoid being damaged.
The dose of the target volume was prescribed in SMART style. The goal was to deliver a total dose of 66-72 Gy to the GTVnx and GTVnd, 60 Gy to the CTV1, and 54 Gy to the CTV2, with fractional doses of 2.2-2.4 Gy, 2.0 Gy and 1.8 Gy, respectively. The radiotherapy plan was delivered in 28-30 fractions, once a day, 5 days a week for 5.5-6.0 weeks. The dose restraints for organs at risk, 40-45 Gy was applied for the brain stem, 35-40 Gy for the spinal cord, 24-30 Gy for the parotid glands, 40-55 Gy for the temporal lobes, 30-50 Gy for the temporomandibular joints, 30-50 Gy for the optic nerves, the optic chiasm, and the pituitary, and 3-5 Gy for the lens. The irradiation dose, volumes of the targets and critical organs were evaluated with the dose volume histogram (DVH). After confirmation by clinicians, the treatment plans were verified through dosimetric test and then delivered in the static IMRT mode (step and shoot) with multiple leaf collimators.
For the 56 patients, the single agent, cisplatin was administered intravenously, 20 mg a day for 5 days and 21 days for a cycle, and accompanied by radiotherapy. For the other 31 patients, the PF plus CF regimen was applied in combination with radiotherapy. The scheme included cisplatin 30 mg/m2 delivered on day 1 to day 3, 5fluorouracil 500 mg/m2 on day 1 to day 5 and calcium folinate 0.1-0.2 g on day 1 to day 5, 21 days for a cycle. In 1 month after completion of the radiotherapy, all the 87 patients received adjuvant chemotherapy with the PF plus CF regimen for 34 cycles. The corresponding data on dose of target volume for all the patients are shown in Table 2.
Dose distribution (cGy) in target volumes.
Follow up
The patients were examined in the 1st and 3rd month after completion of the radiotherapy, and every 3 months thereafter. After 2 years, examinations were done every 6 months. The follow up continued for 1985 months, with the median being 59 months, and was ended in January 2008.
Evaluation of efficacy and toxicity
According to evaluation criteria of treatment efficacy for solid tumors of WHO[3], the outcomes of the patients after treatment were classified as complete remission (CR), partial remission (PR), stable disease (SD) and progressive disease (PD). The acute and chronic toxicities were evaluated based on the Radiotherapy Oncology Group (RTOG) criteria. The SPSS software was utilized to calculate the overall survival rates, local control rates, regional control rates and metastasis free survival rates by the KaplanMeier method. The numerical data were analyzed by χ2 test.
Results
Short-term results
No treatment related death occurred. Eighty-three cases reached CR (95%), and 4 cases were PR (5%), with a total response rate of 100%.
Long-term results
The 1-year, 2-year and 3-year overall survival rates, local control rates, regional control rates, and metastasis free survival rates in both groups differed insignificantly (Table 3).
Survival rates and local control rates in the 2 groups (%).
Evaluation of the acute toxicities
The early side effects were evaluated in the 1st month after completion of the radiotherapy (Table 4).
Acute toxicities caused by combination of SMART and chemotherapy (%).
Evaluation of the chronic toxicities
The late side effects were evaluated in the 12th month after completion of the radiotherapy (Table 5).
Chronic Toxicities of concurrent SMART and chemotherapy (%).
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 1st 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.
- Received June 11, 2009.
- Accepted October 9, 2009.
- Copyright © 2009 by Tianjin Medical University Cancer Institute & Hospital and Springer