The proximity of the nasopharynx to critical normal tissues, such as the brainstem/optic structures, makes it difficult to treat the tumor with two-dimensional techniques while the dose to surrounding organs is kept within an acceptable range.16,17,27
As a result, portions of the tumor were often underdosed with the goal of normal tissue protection. IMRT enables coverage of irregularly shaped tumor while it limits the dose to critical organs, and several single institutions have reported greater than 90% LR control rates.18,21
Lee et al18
reported a remarkable LC rate of 97%, despite around 50% of the patients having T3-4 disease. It is noteworthy that other factors, such as advances in imaging for better tumor delineation, the addition of chemotherapy, and better supportive care, also contribute to the significant improvements in LR control.
Building on the result from University of California, San Francisco, RTOG conducted this phase II trial to test whether the result of IMRT can be reproduced in a multi-institutional setting. Per statistical design, the treatment was considered transportable if less than 10 patients of 57 were scored as having major variations. Because of the protocol requirement for centralized review, it was possible to assess the quality of the target delineation and, when needed, to provide feedback to participating centers on target volume specifications. Consequently, there was a lower percentage of major deviations for the second/subsequent patients entered at a given institution (31% deviation for the first patient, which diminished to 12% with subsequent patients).
Although NPC can be treated effectively with non-IMRT planning techniques, many patients complain of permanent xerostomia as a result of the delivery of a near full dose of RT to the bilateral parotid glands.5,6
The degree of xerostomia is dependent largely on the dose and volume of salivary gland in the radiation field. Studies have shown that salivary flows are markedly reduced after 10 to 15 Gy of RT.30,31
High doses to most of the gland will result in permanent xerostomia, which compromises patient quality of life.32–34
The degree of xerostomia is largely dependent on the dose/volume of the salivary gland in the radiation field.30,31
IMRT can limit the dose delivered to these glands without compromising tumor coverage. Multiple clinical studies have shown a lesser degree of xerostomia after IMRT relative to the two-dimensional technique.18,21
Kam et al19
showed that IMRT had lower incidence of observer-rated xerostomia versus the two-dimensional arm (39.3% v
= .001) at 1 year after treatment for early-stage NPC. There was also higher stimulated parotid flow rate (P
< .001) as well as a higher stimulated whole saliva flow rate (P
= .001) in patients who received IMRT. Pow et al20
showed that IMRT was significantly better than conventional RT in terms of parotid sparing and improved quality of life for early-stage NPC. Although xerostomia and sticky saliva were problems reported in both groups at 2 months post-RT, there was consistent improvement over time with xerostomia-related symptoms at 12 months post-IMRT. This study also showed that only 14% of patients reported grade 2 xerostomia at 1 year from the start of IMRT and that 35% of the patients had no complaints of xerostomia at all.
One of our study end points focused on compliance to combined modality treatment. Our hypothesis was that a potential reduction in the radiation adverse effects on salivary flow by using IMRT would increase patient compliance to combined therapy. We found that 90% of the patients received the full 70 Gy and that 88% of the patients with stageT2b or greater and/or N+ disease received three cycles of concurrent cisplatin. This compares favorably to the compliance rates of 63% in the Intergroup 0099 trial,2
71% in the Singapore randomized trial,12
and 52% in the Hong Kong NPC-9901 trial.11
In addition, 98% of the patients received at least two cycles of CDDP compared with 86% in the Intergroup 0099 trial. Adjuvant chemotherapy compliance to three cycles of CDDP and FU was, however, slightly lower (46% v
55%, 57%, and 76%) in this RTOG study versus in the Intergroup 0099, Singapore, and Hong Kong NPC-9901 trials, respectively. The value of the adjuvant treatment is not clearly known, as at least one study did not include adjuvant chemotherapy also showed superb outcomes.36
Because RT, whether by using IMRT or non-IMRT techniques, with chemotherapy achieved superb LR control in patients who presented with locoregionally advanced NPC, the development of DM has become the main pattern of relapse (up to 30%) and cause of death.18,21,22
The 2-year DM rate of patients who had T2b or greater and/or N+ disease in this series was 18%. This resulted in 2-year PFS and OS of 68% and 77%, respectively. These numbers are similar to the combined therapy arm of Intergroup 0099 trial (3-year PFS and OS rates were 69% and 78%, respectively).2
Given that the predominant pattern of failure in locoregionally advanced NPC treated with IMRT and chemotherapy is DM, and given that patients with NPC who have elevated vascular endothelial growth factor have a higher likelihood of recurrence, DM, and decreased survival, we have embarked on testing the role of antiangiogenic agents to the treatment strategy in this study for this population.37–39
In a recently closed, phase II trial (RTOG 0615), bevacizumab (a monoclonal antibody directed against vascular endothelial growth factor) was added to the concurrent and adjuvant phases of therapy. The reason for combining bevacizumab with the concurrent phase of chemoradiotherapy is to enhance the effect of CDDP in potentially sterilizing distant micrometastases from the beginning of treatment, because compliance to the adjuvant phase has been generally low.
In summary, IMRT with or without chemotherapy produced excellent LPF, RPF, and LRPF rates for NPC. This is the first paper to demonstrate the transportability of IMRT from large institutions to multi-institutional setting. No excessive, unwarranted toxicities have been observed. High rates of compliance to concurrent chemotherapy were achieved, but compliance to adjuvant chemotherapy was poor. Late xerostomia associated with this regimen has decreased. On the basis of the excellent LR control and still-high rates of DM reported in this trial, along with other IMRT and none-IMRT studies, more effective systemic therapy is highly warranted to additionally improve the outcome for these patients.