Quality of life and survival outcome for patients with nasopharyngeal carcinoma treated by volumetric-modulated arc therapy versus intensity-modulated radiotherapy

Over the past decades, advances in modern radiotherapy (RT) techniques for treating nasopharyngeal carcinoma (NPC) have emerged with the development of intensity-modulated radiotherapy (IMRT) or, more recently, volumetric-modulated arc therapy (VMAT). As opposed to the fixed gantry beams used in classical IMRT, VMAT is a novel radiation treatment technique based on volumetric modulated rotational delivery. Dual arc VMAT has been reported to be technically superior, e.g. faster delivery time, use of fewer monitor units (MUs) compared to seven-field fixed beam IMRT in NPC patients, and a dosimetric advantage regarding target volume coverage or sparing some organs at risk (OARs) [1‐3].

Strong evidence has shown that the dosimetric improvement conferred by the technical advance from conventional 2D RT to IMRT in NPC could transfer to clinical benefit, not only regarding toxicity and tumor control, but also in terms of the patient’s QoL and survival [4‐6]. However, whether the therapeutic window of improved QoL or survival in NPC patients could be widened by further technical evolutions of modern RT techniques needs to be evaluated. As far as we know, a clinical comparison has not been reported regarding tumor control, patient survival, or QoL between VMAT and IMRT in NPC patients. In current study, longitudinal results of QoL from NPC patients treated by VMAT or IMRT at a single institution were presented. The data pertaining to QoL were longitudinally collected using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and HN35 module at the four time points: before RT (ti1), during RT (42.4 Gy, 20 fractions, ti2), and 3 months (ti3), and 12 months after RT (ti4). We compared the locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS) and overall survival (OS), as well as the changes of the EORTC QoL scales at the four time points for NPC patients treated by VMAT versus IMRT.

IMRT has been the standard treatment in NPC patients for many years. In the past decades, more advanced RT technique especially the rotational arc technique either by linear accelerator or helical tomotherapy has been made with an attempt to further increment the therapeutic window of RT in treating NPC. Because previous reports suggest the noteworthy incremental improvement in dose distributions of VMAT over IMRT, the comparison of treatment outcome for patients treated by the two techniques becomes encouraging. To our knowledge, this is the first study to compare the clinical outcome for patients with NPC treated by VMAT versus IMRT.

Although nonrandomized but with comparable components of patients, disease and treatment characteristics between both groups in current study, we fail to see a statistically significant improvement in the 3-year LRRFS, DMFS, FFS and OS comparing VMAT with IMRT. Our survival outcome was comparable to the series of VMAT published by Guo et al. [15] or other series of IMRT studies [6, 9, 16]. With identical mean dose at GTV and the three dose levels of PTV between the two groups, it is not surprising that no significant difference in tumor control or patient survival was observed.

Meanwhile, with similar mean or maximal dose of most OARs concerned, we observed no significant difference between the two groups in all the QoL scales at the follow-up time points. The most noteworthy advantage of IMRT or VMAT in the treatment of NPC appears to be related to its ability to preserve salivary function. Salivary dysfunction has been observed to be correlated to the mean dose of parotid gland, and long-term salivary dysfunction is usually preventable if the mean dose of one parotid gland could be spared to less than 20 Gy or both glands spared to less than 25 Gy [17]. With parotid sparing IMRT, many clinical studies have proved the therapeutic benefit of IMRT in preserving salivary function relative to the conventional technique [16, 18, 19]. Whether further reduction of the mean dose in parotids could be achieved by using VMAT in NPC is contradictory in different studies. In our patients, the mean dose of both parotids is around 30 Gy by either VMAT or IMRT. In the study by Lu et al. [1], they compared the dosimetric outcome between the planning of VMAT and IMRT using the same NPC patients and observed a statistically significant reduction (from 31.3Gy to 26.3 Gy) of the mean dose in parotids, however, the result could not be repeated in similar studies reported by Jin et al. [20] or Lee et al. [7].

It is difficult to interpret how much dose reduction of OARs is needed to transfer into the clinical benefits as revealed in the QoL scales in the literature. In a randomized trial to compare IMRT with 2D-RT for early stage NPC, with a remarkable dose reduction of parotids from 61.5 Gy to 32.2 Gy, IMRT results in significantly less observer-rated delayed xerostomia, but not patient-reported xerostomia [19]. In our previous study to compare IMRT with 3D-CRT in NPC patients, with a moderate dose reduction of 12–13 Gy in parotids and oral cavity and 5–8 Gy at the OARs of skull base in IMRT group, a significant improvement in global QoL, fatigue, taste/smell, dry mouth, and feeling ill was observed at the time point of 3 months after RT but the improvement disappeared at the longer follow-up time points [21]. On the contrast, with a mild dose reduction of parotids from 34.1 Gy to 27.3 Gy by helical tomotheapy compared to IMRT, Chen et al. observed a statistically significant difference of 7% versus 38% in their NPC patients who subjectively reported “too little” or “no” saliva at final follow-up [22].

We observed a maximal deterioration of most QoL scales during treatment by IMRT or VMAT, followed by a gradual recovery thereafter. Such a pattern of QoL changes was also observed in other HNC patients following IMRT or 3D-CRT [23]. It has been reported that rehabilitation after multimodal treatment for HNC takes 1 year or more and some QoL scales might have improved considerably, but others, especially in some HNC-specific domains remain compromised [24]. Tribius et al. observed most QoL scales would return to the baseline level but some residual deficits, e.g. dry mouth and sticky saliva were still persistent 1 year later for locally advanced HNC patients treated by definite IMRT [25]. For NPC patients treated by IMRT or VMAT as revealed in the study, we observed global QoL and social functioning recovered to significantly better than the pre-treatment status, but the symptomatic scales in swallowing, taste/smell, opening mouth, dry mouth, and sticky saliva were still worse. Changes in QoL following treatment might reflect the combined effects of tumor regression and treatment related complications that patients have perceived. Before treatment, patients had just received the catastrophic information of being diagnosed with cancer and were facing a possibly life-threatening treatment, which might have great impact on their global health status. After having finished the treatment, experienced tumor shrinkage, and recovered from acute side effects, they had time to adapt to the situation, though some late complications in head-and-neck area still remained. Furthermore, the adaptation process called response shift might have occurred during the recovery process, and patients might have reappraised their life domains and altered satisfaction with life themes [21].

With lack of randomization, this study has several limitations. We cannot rule out the presence of some unmeasured confounding factors (e.g. the positional or volumetric changes during the treatment course) between the two groups and the inevitable bias imposed by different operators of the treatment planning systems. Except for the mean dose, detailed dosimetric data were not provided in the cohort; therefore, it was difficult to establish the specific dose-response relationship at the target and OARs that might have contributed to the clinical outcomes observed between the two techniques. In the study, the orthogonal KV X-ray images were used to perform the daily image guidance to overcome organ motion and daily treatment set-up uncertainties, which could potentially be improved by daily cone beam CT or MR guidance [26, 27].

In conclusion, the study provides the evidence that the tumor control, survival and changes of QoL is compatible for NPC patients treated by VMAT versus IMRT.