In this study, for the first time, IMRT and concurrent TP regimen was demonstrated in patients of upper esophageal cancer, and had shown a promising activity. Our data showed that this strategy for patients with upper esophageal cancer produced clinical outcome, which was not worse than those results previously reported in esophageal cancer.
The concurrent CRT has been increasedly used as primary therapy regimen in patients who had unresectable esophageal carcinoma, were unwilling to undergo surgery, or were medically unfit for surgery. The RTOG 85–01 trial firstly analyzed the efficacy of CRT as a definitive treatment and revealed the superiority of CRT over radiotherapy alone in regards to 5-years overall survival . Furthermore, Wong et al. found that concomitant CRT is better than sequential CRT when a non-operative approach is selected for patients with localized esophageal cancer by meta-analysis. On these bases, several researchers investigated the optimal therapies strategies to prolong the survival and improve patient’s quality of life. A landmark study (INT 0123) found that combined-modality therapy consisting of 5-FU and DDP with concurrent 64.8 Gy was not better than the same regimen with concurrent 50.4 Gy in survival (13.0 vs. 18.1 months) and local/regional control (56% vs. 52%) . In an attempt to improve these results, the RTOG 0113 phase II trial was designed to compare two different chemotherapy regimen including 5-FU, DDP and paclitaxel with concurrent 50.4 Gy of radiation in patients with localized esophageal cancer . Although 5-FU-based group seems better than non-5-FU-based group and the result of INT 0123 study, it did not achieve the desired 1-year survival mark. Also, the two groups have 80% rate of grade 3 or 4 toxicities. Treatment-related death occurred in 3% and 6% of patients in two arms relatively. Therefore, neither of the two kinds of CRT strategies consisting of paclitaxel plus DDP proved to be sufficiently superior to the historical control of INT 0123 and warranted further investigation. In our study, the median OS was 18.0 months, which was relative higher than the results reported in TP-based group of the RTOG 0113 study (18 vs. 14.9 months). In addition, the grade 3 or 4 toxicities in our study were obviously lower than it, although the rates of the treatment-related death were similar (5.5% in our study and 6% in RTOG 0113 study). The reasons why this significant difference existed in two studies might be summarized as following: 1. the dose and time of TP regimen were different in two studies, and our regimen seemed more moderate; 2. 66% (23/35) of the patients in the TP-based CRT group of the 0113 trial were dignosed with the adenocarcinoma, while our patients were all squamous-cell esophageal carcinoma. The different pathological types might result in different response to CRT and the survival. However, our response rate was relatively low especially for CR rate when compared to those data reported previously. The possible reason might be the different chemotherapy schedule. In the previous studies, TP regimens were all scheduled weekly while ours was 3-week based plan. Moreover, surgery was performed in these studies that might have an impact on the results as well.
Most reported literatures about CRT of upper esophageal carcinoma have explored various combined-modality therapeutic schedules. Wang et al. reported significant results from a single institution experience of concurrent chemoradiation in 35 patients of cervical and upper thoracic esophageal cancer . Median radiation dose was 50.4 Gy/28 fractions, and chemotherapy was 5-FU based. After a median follow-up of 39 months, the median PFS was 6 months and OS was 13 months. In addition, they showed that patients who received a radiation dose of greater than or equal to 50 Gy had a better outcome than those who received less than 50 Gy. In a recent study , the OS for patients in the up-front chemoradiation group was 24.9 months and the 2-year survival rate was 46.9%. The overall survival was very good probably because surgery followed CRT in 6 of 21 patients. Huang et al. reported their study compared the results of CRT based on 5-FU and either mitomycin C or DDP with 54 Gy of radiation with the high-dose DDP and 70 Gy of conformal radiation . For all patients, the OS rate at 2 and 5 years were 46% and 28% in these patients treated curatively, respectively. However, no survival improvement could be showed after changing the treatment policy to high-dose cisplatin based and conventionally fractionated conformal radiotherapy.
To our knowledge, there were two studies investigated the TP regimen combining the conformal radiotherapy for esophageal carcinoma [26, 27]. Both of them reported the weekly paclitaxel (intravenous infusion) and DDP with concurrent radiotherapy for esophageal carcinoma, some of these patients followed by surgery. Although the regimens were different between their studies and ours (3-week based), the outcomes still indicated that the TP regimen combined with radiotherapy for esophageal carcinoma was effective and tolerable.
In our study, all acute toxicities were tolerable (Table 3). The most common treatment-related toxicities included the radio-dermatitis and radiation-induced esophagitis. We had not observed the late-phase toxicities (such as pneumonitis, pleural effusion, and cardiac effusion), the reason might be that only partial volume of the lungs and heart had been irradiated during IMRT treatment. But one issue should be addressed here. In our study, two patients died because of esophageal perforation and hemorrhea after CRT. As reported in the RTOG 0113 trial, the majority of late radiation toxicities were related to esophageal injury . We found that the huge ulcers (diameter ≥ 2 cm) were showed in the lesions of two patients. It seemed to suggest that those inevitable esophageal perforation and hemorrhea should be paid more attention in concurrent CRT for ulcerated carcinoma in practice.
In conclusion, our results showed that IMRT combined with concurrent TP regimen chemotherapy could be considered as an effective treatment with no significant toxicity in those patients with upper esophageal carcinoma. Currently, because all studies were small and retrospective, more studies on larger population are required to determine the specific treatment approach in upper esophageal carcinomas.