The superiority of IC-CCRT combined with radiation in patients was first demonstrated in the landmark which replaced chemoradiotherapy alone with induction platinum-based chemotherapy followed by concurrent high dose cisplatin with radiotherapy.13 The scheme of induction therapy can effectively alleviate the lesions and create improved radiotherapy conditions for LANPC, especially in patients with giant lesions, achieving better survival and prognosis. However, one of the outcomes of induction chemotherapy can increase radiation-induced toxicities and adverse events, such as dermatitis or oral mucositis.14,15 There is currently no well-defined standard of care in the management of patients with radiation-induced acute injuries. Radiation-related injury, which frequently occurred in patients treated with NPC, could cause physical and mental suffering due to pain, ulcer, exudate, various cosmetic problem and reduced quality of life.16,17 To reduce acute toxicity, a better focusing of radiation were actively studied and avoiding the integument. IMRT and 3D-CRT have been demonstrated an improved treatment outcome and lower skin toxicity in other head and neck cancer, they are the primary radiotherapy techniques for cancer patients during recent decades.18 However, the prevalence of radiation-related complication with induction chemoradiotherapy in the current literature varies widely.19–21 There is still a lack of evidence and controversy comparing IMRT with 3D-CRT for LANPC. To the best of our knowledge, there is no randomized controlled comparison for IMRT vs. 3D-CRT in LANPC treated with IC-CCRT bringing about acute toxicity. For this reason, we should pay attention to injury-sparing IMRT and 3D-CRT, which is an active method to reduce radiation-related acute toxicity. The investigation of the occurred timing for acute adverse events will be benefit to prevent these radiation-related toxicities during the treatment.22 The purpose of this study was to provide a comprehensive description of radiation-induced toxicity rates and acute side effects for IMRT vs. 3D-CRT in LANPC with platinum-based IC-CCRT.
Notably, the present study is the first to prospectively measure and report the occurred time of acute toxicity after initiation of radiation treatment and comparison for two irradiation techniques within the analysis of a Cox proportional hazards model. That provided a new method for further study between radiation injury and radiotherapy in cancer patients after then. Our novel finding of a differential effect between the toxic risk of 2–6 weeks and the proportion of acute injury on the treatment compared with 3D-CRT that IMRT may confer a substantive disadvantage to patients been put off treatment plan for bringing forward adverse events. A Cox proportional hazards model of this study stated less bone marrow toxicity and worse gastrointestinal control, a trend toward earlier occurred white blood cell toxicity in patients treated with IMRT.
Acute skin toxicity in the form of radiation dermatitis or skin hyperpigmentation is a common problem experienced by patients undergoing NPC irradiation. The most common acute adverse events were oral mucositis and dermatitis, which occurred in 96.43% and 88.84% of the patients, the earliest occurrence of oral mucositis was observed during the treatment. A possible explanation for these results may come from susceptible to external infection and close-range irradiation. A phase III randomized trial of IC-CCRT in patients with locally advanced head and neck cancer stated that the most common toxicities were mucositis and dermatitis.23 In our study, the incidence rate of these adverse events was not in contradiction to previous reports. Levy et al also reported that the highest morbidity of acute toxicity was dermatitis (97%) with concurrent radiotherapy and cetuximab after taxane-based induction chemotherapy in locally advanced head and neck cancer.24 Concurrent chemotherapy in NPC treated with neoadjuvant chemotherapy followed by IMRT was exhibited 48.3% dermatitis, 49.2% oral mucositis, 38.1% bone marrow toxicity, 40.9% xerostomia and 21.2% nausea vomiting.25 There are more than 40% of patients occurred severity acute injuries for most of locoregional advanced cancer during treatment in previous studies. The investigation of IMRT dose distribution to the skin in head and neck squamous cell carcinoma was reported the incidence of grade 3 and 4 radiation dermatitis was 41.1% in patients included and 50% vs 36.6% in the cetuximab and cisplatin cohorts, respectively.26 Grade 3–4 hematologic toxicities and radiotherapy-related oral mucositis during the period of locoregionally advanced nasopharyngeal carcinoma treated with nimotuzumab plus IMRT with chemotherapy were reported in 7.4% and 10.9% patients, and there were only 8.6% patients who complained of serious xerostomia.27 The patients experienced severity toxic effects or cannot tolerate it during irradiation, which would either delay or suspend treatment. Nevertheless, it appears that wide rate of radiation-induced acute injuries may speculate on radiation technique, chemotherapy scheduling and the location of tumor.
Several studies have revealed that IMRT could provide reduced irradiation to the normal tissue without compromising target volume coverage, which is an advantage of the technique.28 Data directly comparing acute side effects of NPC patients treated with IMRT and 3D-CRT are lacking in the literature as well, but lower rates of wound healing complications with IMRT were referred to more recent studies.18 In our study, reduced hyperpigmentation and bone marrow toxicity appeared more remarkable in light of the treatment performed in the IMRT group than those of the 3D-CRT group and this difference remained robust in a univariate and multivariate analysis. As E. Hardee et al demonstrated that IMRT moderately decreased rates of subacute hyperpigmentation for hypofractionated whole-breast radiotherapy at 1 month of follow-up.29 Under this, IMRT had possessed a more homogenous dose distribution, which was reported as a good alternative to treat cervix carcinoma with bone marrow toxicity.30 The clinical trial was demonstrated that the cause of thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection, which was possibly caused by improvement of hypersplenism and HCV-induced bone marrow toxicity resulting from anti-HCV therapy.31 Acute dermatitis and oral mucositis of the two groups were not obvious different in our study. This may have been because of strictly controlled other variables between radiation techniques. Ghosh–Laskar et al also showed that there were no significant differences in the incidence of some acute toxicities between IMRT and 3D-CRT, such as mucositis, dermatitis and dysphagia, which is in good accordance with our findings.32 Borm et al released that 3D-CRT allows a homogeneous dose distribution with similar skin toxicity as compared to studies performing IMRT with chemotherapy.10 Furthermore, a Cox proportional hazards model suggested that oral mucositis and dermatitis are truly driven by the selected IC 5-FU treated scheme or others. This can be attributed to the fact that the extra regimens of IC-CCRT may have weakened the protective effect of IMRT on the skin. However, there are some findings of previously reported studies different from above results. Liang et al concluded that dose homogeneity across nasopharyngeal in the IMRT plan can reduce the adverse effects related to the acute skin toxicity of patients according to the RTOG toxicity criteria.33 Katano et al analyzed various radiation-related factors in terms of cosmetic outcome and found that the radiation techniques and doses delivered to the nasopharynx were statistically significant factors.34 Comparing with 3D-CRT, patients treated with IMRT for anal carcinoma had a significantly lower degree of skin toxicity and higher rate of acute diarrhea, but rates of hematological toxicity and proctitis were not reduced.18 Comparison of toxicities demonstrated that IMRT was a safe regimen with less xerostomia, acute dermatitis and favorable locoregional control, survival rates during treatment of locally advanced oropharyngeal carcinoma.35 Since acute side affections frequently limit radiation treatment, IMRT might have enabled more aggressive treatment in some patients.
However, not all side effects of radiotherapy were superior in the IMRT group. We noted a significantly increased rate of gastrointestinal injury and leukopenia upon IMRT, observed in univariate and multivariate analyses, which is not entirely clear. One possible explanation could be a different distribution of radiation in the small intestine. This difference with higher treatment rates and dosages for 5-FU and docetaxel drugs in the IMRT group, might to some extent explain the increase in acute diarrhea in the IMRT group. There was a study also reported a trend toward more gastrointestinal toxicity in IMRT.18 In addition, our study also demonstrated a trend toward higher hematological toxicity in the IMRT group. In contrast to that, lower hematological toxicity for IMRT compared to 3D-CRT for the treatment of cervical cancer was demonstrated in some studies. Strikingly, our multivariable analysis found that the negative impact of IMRT to leukopenia was comparable, which greater than the effect of these chemotherapy drugs on these toxicities. This finding is different from the result of Chi-square test and fully shows the superiority of Log-rank method. As shown in a simulation by Kuma et al, a cohort of cervical cancer patients receiving definitive chemoradiation was assessed that more frequent severity leukopenia was found in the IMRT group.30 As induction and concurrent chemotherapy are the major part of the treatment, which cannot be ignored, the suggestion of this study is to minimize un-necessary irradiation dosage to decrease hematological toxicity.
Our data suggest better local tumor control upon IMRT treatment. Apparently, IMRT allows a more localized focus of radiation in the primary tumor area which might have received more radiation volume and more homogenous radiation over its entire volume for maximum oncological effects. However, previously reported studies with NPC have suggested that IMRT gives at least the same outcome in primary tumor as three-dimensional conformal techniques.21 In addition, highly similar survival outcomes for IMRT and 3D-CRT had reported in most studies as our study showed. Yan et al concludes that IMRT and 3D-CRT have almost the same short-term and long-term clinical effects in the treatment combined with postoperative chemotherapy of nasopharyngeal carcinoma and both of them have high effectiveness and safety.36 No survival benefits had been observed while comparing IMRT versus 3D-CRT in cervical esophageal squamous cell carcinoma patients treated by concurrent chemoradiotherapy.37 A National Cancer Database Analysis reports that there was no difference in OS for patients who received IMRT versus 3D-CRT, IMRT was associated with similar survival as 3D-CRT.38 Another meta-analysis showed that the 3-year OS, DFS rates had no significant difference between the IMRT and 3D-CRT groups for gastric cancer, but IMRT might be superior to 3D-CRT in treating patients with gastric cancer in terms of local control rates.21 But beyond that, there are also studies of IMRT patients had better tumor control than 3D-CRT with equal or better oncological results for anal carcinoma patients.18 A meta-analysis provided the results that IC-CRT should be the most suitable regimen for LANPC in the IMRT era.39 Improvement of survival in our study upon IC-CCRT treatment is encouraging.
Some limitations must be considered for this study. Taking a full account of the occurrence of radiation-induced acute injury is valuable. However, the grade 3 or worse of dermatitis or oral mucositis had been not investigated their deterioration time during the treatment. The severity acute injuries may better report the impact of side effects between IMRT and 3D-CRT on the treatment of patients. Nevertheless, our data provide a real-world experience on adjuvant therapy except IMRT or 3D-CRT might change outcome and side effects in radiochemotherapy for LANPC. Acute toxicity should be analyzed with caution as the follow-up of patients treated by IMRT is lower than that of 3D-RCT group. However, no difference in survival was noted between the groups. The number of tumor relapses significantly different may be explained by the difference of follow-up between the groups.