Analysis of simultaneous modulated accelerated radiotherapy (SMART) for nasopharyngeal carcinomas

The purpose of this study was to analyze the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) in patients with nasopharyngeal carcinoma (NPC). A total of 97 patients who underwent SMART for NPC between August 2005 and November 2011 were evaluated. The prescribed dose was 69.9 Gy/30 fractions at 2.33 Gy/fraction to the primary gross tumor volume (PGTV) including the nasopharynx gross target volume and the positive neck lymph nodes, and 60 Gy/30 fraction at 2.0 Gy/fraction to the PCTV1; 54 Gy/30 fractions at 1.8 Gy/fraction was given to the PCTV2. Among 59 patients with local advanced disease, 31 patients received concurrent chemoradiotherapy (chemo-RT) with a regimen consisting of 135 mg/m2 paclitaxel on Day 1 and 25 mg/m2 cisplatin on Days 1–3. The median follow-up period was 42 months. The local control rate (LCR), distant metastases-free survival (DMFS) and overall survival (OS) rates were 93.3%, 90.3% and 91.6% at 3 years, and 87.6%, 87.9% and 85.7% at 5 years, respectively. There was no significant difference in outcome with respect to these three indicators for Stage III and IV disease treated with/without concurrent chemoradiotherapy (P > 0.05). Acute toxicities included Grade 3 mucositis, skin desquamation, and leucopenia, which occurred in 78 (80.4%), 8 (8.2%), and 45 (46.4%) patients, respectively. No patient had a Grade 3–4 late toxicity. SMART was associated with a favorable outcome for NPC with acceptable toxicity. The local-regional control was excellent but distant metastasis remains the main risk. The combination of SMART and chemotherapy needs to be optimized through further studies to enhance outcomes for locally advanced diseases.

We sought to improve the cure rate by increasing the biologically effective dose to the boost volume, and designed a regimen of 2.33 Gy for a total of 69.9 Gy with the use of IMRT with SMART boost techniques. The aim of our study was to evaluate the long-term local control, survival, and concomitant toxicities of this technique delivered at our dose scheme, with or with concurrent chemotherapy, for the treatment of NPC.

Common conditions
Between August 2005 and November 2011, a total of 97 eligible patients were enrolled in this study. The patients had to fulfill all of the following criteria including: (i) histologically confirmed NPC by biopsy, (ii) no evidence of distant metastasis, (iii) no previous treatment for NPC, (iv) adequate liver and renal function, (v) adequate bone marrow function, and (vi) Karnofsky performance status ≥ 80.
The pretreatment evaluation consisted of a complete history and physical examination together with a nasopharyngoscopy, chest radiography, ultrasonography of the abdominal region, and hematologic and biochemical profiles. Additional investigations including emission computed tomography (ECT) and positron emission tomography (PET) were performed before initiation of treatment if there was a suspicion of metastasis. After March 2009, magnetic resonance imaging (MRI) of the nasopharynx was required to determine stage unless there was a contraindication. Prior to that time, MRI and contrast-enhanced computed tomography (CT) of the nasopharynx were alternatively performed to determine stage. As this trial was initiated in September 2005, patients were initially staged according to the 2002 AJCC/UICC system in our protocol. After the publication of the 2009 AJCC/UICC system, all of the enrolled patients were restaged according to the 2009 AJCC/UICC criteria. The demographic and clinical characteristics of the patients are shown in Table 1. Written informed consent was obtained from all patients. The protocol was approved by the ethics committees of the participating institutions, and the trial was conducted in accordance with the Declaration of Helsinki.

Treatment
Patients were immobilized in the supine position with a thermoplastic mask from head to neck, and a contrast-enhanced CT simulation was performed with a slice thickness of 3 mm extending from the vertex to carina of the trachea. If possible, fusion of MRI and/or PET with the planning CT images was performed to aid in the delineation of the gross tumor volume (GTV). All target volumes were outlined slice by slice on the axial contrast-enhanced CT images in the treatment planning system. The target volumes were defined in accordance with the International Commission on Radiation Units and Measurements Reports 50 and 62 [10][11]. The GTV included the primary disease and nodes greater than 1 cm in diameter or nodes with necrotic centers. The clinical target volume (CTV) was divided into two parts: CTV1 and CTV2. CTV1 was defined as the nasopharynx gross target volume plus a 5-8-mm margin (1-3-mm margin posteriorly) to encompass the high-risk sites of microscopic extension and the whole nasopharynx. CTV2 was defined as the CTV1 plus a 5-10-mm margin (1-3-mm margin posteriorly) to encompass the low-risk sites of microscopic extension, the level of the lymph node located, and the elective neck area (bilateral retropharyngeal and Levels Ib, II, III and Va are routinely covered for all N0 patients, whereas bilateral Levels IV and Vb were also included for N1 patients). Planning target volumes (PTVs) for all GTVs and CTVs were generated automatically with a 3-5-mm margin after delineation of tumor targets in order to include biological and technical uncertainties. The margin was applied in all dimensions except posteriorly, where a 1-3-mm margin was used because there is less biological uncertainty at the skull.
A total of 97 patients who underwent SMART for NPC between August 2005 and November 2011 were evaluated. The prescribed dose was 69.9 Gy/30 fractions at 2.33 Gy/ fraction to the PGTV (including the nasopharynx gross target volume and the positive neck lymph nodes) and 60 Gy/30 fractions at 2.0 Gy/fraction to the PCTV1; 54 Gy/ 30 fractions at 1.8 Gy/fraction was given to the PCTV2. In our department, we use the step and shoot technique for For patients with extensive locoregional disease, the addition of concurrent chemotherapy is a standard recommendation based on the survival benefit [12]. In our study, 59 patients with extensive locoregional disease (Stage III, IVa and IVb) were divided into two groups at random: one group receiving concurrent chemotherapy and the other group receiving induction chemotherapy only and/or adjuvant chemotherapy. The regimen consisted of 135 mg/m 2 paclitaxel on Day 1 and 25 mg/m 2 cisplatin on Days 1-3 instead of cisplatin for concurrent chemotherapy, and the same regimen was also applied for induction chemotherapy and adjuvant chemotherapy. Induction chemotherapy was given in one to two cycles and adjuvant chemotherapy given in four to six cycles. Patients in the concurrent chemotherapy group received one cycle of chemotherapy which started simultaneously with radiotherapy, and whenever possible these patients also received induction chemotherapy and/or adjuvant chemotherapy. Comparisons of the demographic and clinical characteristics of the two groups are shown in Table 2.

Follow-up and statistical analysis
Planned patient assessment post-treatment included indirect nasopharyngeal speculum examinations and a fiberoptic nasopharyngoscopy every 3 months for the first year of follow-up, every 6 months in the second and third years, and annually thereafter. A follow-up CT or MRI scan of the nasopharynx and neck was performed approximately every 6 months from the completion of radiation therapy for the first 3 years. Afterward, an annual CT or MRI scan was obtained.
During every follow-up visit, disease status and treatment toxicity were assessed. A suspected recurrence was histologically proven unless a biopsy would cause an excessive risk of injury to the patient. Biochemistry profiles, chest radiography and abdominal ultrasonography were routine elements of the assessment. Further investigations were arranged as indicated. Patients were classified as progression free as long as they remained alive without local, regional or distant recurrences.
The Kaplan-Meier method was used to calculate actuarial rates of local control, distant metastases-free survival (DMFS), and overall survival (OS). Late toxicities were graded according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria [13]. All time-to-failure endpoints were calculated from the date of the end of treatment to the date of failure/last follow-up for patients who did not experience failure. Patients who developed distant metastases were still observed for locoregional failure.

Local control and survival
Radiation therapy was completed without interruption in all patients. Every patient received the prescription dose of 69.9 Gy to the gross disease and was regularly followed up until death or 31 December 2012. Of the total patients, 42 received radiotherapy together with concurrent chemotherapy as planned, 19 received radiotherapy with no chemotherapy, and 36 received only induction/adjuvant chemotherapy. The median duration of follow-up was 42 months (range, 13-88 months).
At the time of the analysis, treatment failure was seen in 18 patients. Eight (8/18) of these patients experienced local recurrence, two (2/18) had cervical lymph node recurrence, nine (9/18) had local-regional recurrence, and ten (10/18) developed distant metastasis. The details of treatment failure of the patients are shown in Table 3. All local recurrences were in-field failures within the nasopharynx gross target volume. For the patients with local recurrence, we gave a second course of radiation with IMRT and achieved satisfactory results; five (5/8)   Indicates existence. c mo = month.  Table 4. The most commonly observed severe (i.e. Grade 3 or 4) acute toxicities included Grade 3 mucositis, skin desquamation, and leucopenia, which occurred in 78 (80.4%), 8 (8.2%), and 45 (46.4%) of the 97 patients in the study, respectively. No patient had a stomach tube inserted or a gastrostomy before or during treatment for nutritional support. Grade 3 acute skin toxicity developed in 10% of the patients, but no Grade 4 skin toxicity was observed. One patient presented Grade 4 leucopenia. The total incidence of Grade 3 or 4 acute toxicities in patients receiving IMRT plus concurrent chemotherapy was 86.0%, significantly higher than those receiving IMRT alone (59.8%) (P < 0.005).
Late toxicities were assessed in 40 patients with > 3 years follow-up. The results are depicted in Table 5. The most common late toxicities were hearing loss, trismus and xerostomia. No patient had Grade 3-4 late toxicity. Xerostomia was assessed in all patients during follow-up. Grade 1 xerostomia had developed in 47.5% of patients and Grade 2 xerostomia in 5% of patients at a median follow-up of > 36 months. The severity of xerostomia diminished over time after treatment. The number of patients with Grade 2-3 xerostomia decreased gradually, whereas the number of      [9,[26][27][28][29][30][31][32][33]. It seems that the short-term results reported in those series were all quite good. However, the fraction dose ranged from 2.09-2.5 Gy, and the total physical dose ranged from 68-79.5 Gy. After we transformed the physical dose into BED, the BED ranged from 83.4-97.5 Gy. We found that the BED of the nasopharynx gross target volume in our series was similar to the BEDs in Bakst et al.'s series [33], which were 86.2 Gy and 86.6 Gy, respectively, whereas the BEDs reported by other authors ranged from only 83.4-84.8 Gy [27-28, 30, 32]. By contrast with their result, our result seems to be quite good. Some series [26,29], whose BEDs were much higher than ours, have greater LCRs than ours, while Xiao et al.'s [9] result was no better than ours, although the BED in their study was obviously higher than ours. Compared with studies that only enrolled patients with advanced TNM classification [9,29,33], our outcomes still seem to be better. Many T4 patients remain free of disease at last follow-up, suggesting that they might have benefited from the hypofractionated approach. The results are detailed in Table 6. Furthermore, most of the studies integrate other techniques to boost the dose after IMRT, such as brachytherapy [26,31], SRS [29], 3DRT, and IMRT [27,28]. Considering all the above factors, the local control achieved in our study is quite satisfactory, with 3-and 5-year LCRs of 93.3% and 87.6%, respectively. This implies that IMRT with the SMART boost technique, using our dose scheme to enhance the BED of the nasopharynx gross target volume, may be a better choice to improve the local control of disease for patients with NPC.
Chemotherapy also has an important role in the treatment of NPC alongside RT. Intergroup 0099 established the role for chemoradiotherapy in the treatment of NPC [12]. Multiple randomized Phase III trials that followed have shown an advantage for concurrent chemo-RT in locally advanced NPC, although the chemotherapy generally consisted of cisplatin-based chemotherapy in most of the studies [5,[34][35][36][37]. Chitapanarux [38] used carboplatin instead of cisplatin for concurrent chemoradiotherapy to treat 206  locoregionally advanced NPC patients, and although the compliance of patients in the carboplatin group was better, no significant difference was noticed in treatment efficacy between these two arms. Kwong [39] reported a trial which used uracil and tegafur (600 mg daily) as concurrent with adjuvant chemotherapy of CDDP/5FU + VBM for three cycles; they found a significant improvement in the DMFS (P = 0.026), with a similar trend in both OS (87% vs 77%) and progression free survival (69% vs 58%). But attention should also be given to compliance and toxicity accompanying concurrent and adjuvant chemotherapy, because within the intergroup 0099 trial only 55% of the patients completed adjuvant chemotherapy [12]. The chemotherapy regimen we used contained 135 mg/m 2 paclitaxel on Day 1 and 25 mg/m 2 cisplatin on Days 1-3 instead of cisplatin for concurrent chemotherapy, and the same regimen was also applied to induction chemotherapy and adjuvant chemotherapy, which is widely used for head and neck cancers. Toxicity was acceptable in both groups. Although a trend of improvement in LCRs (100% vs 82.6%) was seen, there was no statistically significant difference between the concurrent chemo-RT group and the no chemo-RT group for LCR, DMFS or OS. Adequate chemotherapy has been shown by meta-analysis [40] to decrease local/distant failure and to improve the survival of patients with locoregionally advanced NPC. In our regimen, the paclitaxel dose was reduced to 135 mg/m 2 on Day 1 and the cisplatin dose was reduced to 25 mg/m 2 on Days 1-3 to reduce toxicity. Therefore, we speculate that the limited chemotherapy used in this trial is quite likely to be the reason for the less than satisfactory LCR, DMFS and OS rates. A higher-dose chemotherapy regimen for a larger population of patients will be included in a further study. In our study 31 patients received concurrent chemotherapy, the 5-year OS was 84.0%, and distant metastasis was the major cause of death in patients after treatment. Although concurrent chemotherapy is generally accepted to be the standard of care for locoregionally advanced NPC, the best chemotherapy regimen remains debatable. In our study, we found that the accelerated regimen did result in increased acute toxicities of the skin and mucous membranes, but with anti-inflammatory therapy and nutrition support, no patient required significant treatment breaks and all patients finished treatment. We also observed a few significant late toxicities. Grades 1 and 2 toxicities were observed in 40 patients over 3 years of follow-up, but no patient had Grade 3-4 toxicity. The lower incidence of deafness, trismus, temporal lobe necrosis, neuropathy, dysphagia and xerostomia in our current cohort was especially dramatic compared with the long-term toxicities in previous retrospective and prospective investigations [41,42]. As was reported in other studies [26,27], xerostomia appeared to decrease with time after treatment. The incidence of trismus was quite low. Several reports [9,33] have indicated the occurrence of temporal lobe necrosis. It is worthwhile to note that no temporal lobe necrosis was detected in our trial, although 12% of patients developed this kind of injury in Bakst et al.'s trial [33] (in which patients with NPC received almost the same technique of radiotherapy as our patients). Temporal lobe necrosis may be the result of extensive invasion of the skull base and even intracranial tissue, which led to increased doses to the temporal lobes. We found that the ratio of patients with T4 disease in the two trials were similar (21.6% vs 20.0%), however, only three (3.1%) of the patients suffered from intracranial extension in our group. Also, Bakst et al. found the median time till detection of temporal lobe necrosis after radiation was 24 months (range, 19-48 months). For the three patients with intracranial extension in our group, the follow-up times were 14 months, 25 months and 37 months, respectively, which was relatively shorter, I think. Maybe those above were the difference between the two trials. However, the specified dose constraints to the temporal lobes and a modified PTV to limit the dose to the temporal lobes were still rather important. So in our view, the regimen of 2.33 Gy for a total of 69.9 Gy with the use of IMRT with SMART boost techniques still seems to be safe with respect to temporal lobe necrosis. All these results suggest that potential functional gains from SMART boost IMRT with our fractionation scheme restricted the dose delivered to the normal tissue around the tumor and resulted in decreased rates of severe late toxicities, thus improving the quality of life.

CONCLUSIONS
Long-term outcomes for NPC patients who underwent IMRT with the SMART boost technique in our study demonstrate excellent LCR, DMFS and OS with acceptable and tolerable treatment-related toxicities. However, no improvement was noted in LCR, DMFS or OS using concurrent chemoradiotherapy that contained paclitaxel and cisplatin as our chemotherapy regimen, and distant metastasis was still the major cause of treatment failure in our study. Although further research is required, there is a trend in the clinical data that suggests an enhanced therapeutic ratio and a possible survival advantage for this modality of radiation therapy. A larger population of patients and a longer followup period are needed to evaluate ultimate tumor control and late toxicity. New strategies identifying the best dosage for an optimal chemotherapy regimen to enhance the therapeutic effect of chemoradiotherapy need to be developed in further studies.