Definitive radiochemotherapy in esophageal cancer - a single institution experience

Nowadays, the preoperative radiochemotherapy (pRCT) followed by surgery is the standard treatment for squamous cell cancer and adenocarcinoma of the esophagus in the stage ≥ T1b–2N0M0, with perioperative chemotherapy being one of the treatment options for adenocarcinoma, as well.1, 2, Based on the results of the RTOG 85-01 study, since the late nineties of the last century, definitive radiochemotherapy (dRCT) became another viable treatment option for patients with locoregionally advanced esophageal cancer.3 It is reserved for the patients who are not fit for surgery or decline it and is a preferable treatment option for patients with tumors located in the upper third of the esophagus (cervical tumors), since surgery procedures in these patients can be associated with significant postoperative morbidity and mortality.1,2 Before that, patients with inoperable esophageal cancer were usually treated with paliative intent or best supportive care only. Survival results for pRCT followed by surgery can reach up to 50% at five years with a locoregional control rate of up to 85%.4 For dRCT five year survival is around 25% and locoregional control is about 40–60%.5 In recent years, in patients treated with dCRT, there was not much improvement in survivals, but with multidisciplinary approach, use of modern radiotherapy techniques (such as intensity modulated radiotherapy [IMRT] or volumetric arc therapy [VMAT]) and different chemotherapy regimens given (paclitaxel/ carboplatin), there was improvement in reducing treatment related toxicity with consequent better quality of life during and after the treatment.1, 2, 6, 7, 8

In Slovenia, in all newly diagnosed esophageal cancer patients, the treatment decisions are provided by multidisciplinary board committees. If the treatment with radical intent is proposed, all the patients are treated in the Institute of Oncology Ljubljana (IOL) which provides the chemo- and radiotherapy part of the treatment protocols and/ or in the University Clinical Centers in Ljubljana and Maribor, where surgical procedures are performed. The selection of patients suitable for dCRT is based on the results of pretreatment diagnostic procedures (tumor location, histology, TNM stage), performance stage (WHO stage ≤ 2) and eventual comorbidities (e.g. significant renal, hepatic or bone marrow impairment), which could have an impact on the chemotherapy given.

The aim of this retrospective study was to evaluate the treatment results of dRCT for patients treated in the IOL in the period from the beginning of 2010 to the end of 2017.

Esophageal cancer is a disease which predominantly affects older men with a history of smoking and alcohol abuse (squamous cell cancer) or patients with obesity and history of gastroesophageal reflux and/or Barret’s esophageal metaplasia (adenocarcinoma).7 Nowadays, dRCT is one of the possible treatment strategies used in esophageal cancer of both histologies. The indications for its use are well defined in national and international guidelines for the treatment of patients with esophageal cancer.1, 2, 10 It is reserved for patients with inoperable tumors of the lower two thirds of the esophagus, patients who decline surgery and is a preferable treatment option in patients with tumors located in the cervical esophagus. Since dRCT can be accompanied by serious treatment side-effects, the careful selection of patients is necessary. In our group of patients, 58.2% of them had tumors in the cervical esophagus and/or synchronous head and neck cancers and in the remaining 23 patients, the tumor was locally advanced (T3 or T4) in 20 (86.9%) patients. 90.9% of all the patients included in our study were in a good general performance (performance stage 0-1 according to WHO scale). In the retrospective study of Haefner et al. in the group of 93 patients treated with dCRT the tumor was located in cervical, upper or mid esophagus in 66.7% of patients.11 Seventy-two (77.2%) patients had T3-4 tumors and most of them were in a relatively good general condition with the mean Karnofsky performance status of 86 (range: 70–100).

Because of the natural course of the disease which primarily affects the swallowing, special attention needs to be addressed to patients’ pretreatment evaluation of alimentary status and adequate nutritional support during the treatment.12 In our group of patients, 49 (89.1%) patients had problems with swallowing and/or were aphagic at diagnosis and consequently in 60% of patients some kind of surgical intervention (dilation or esophageal stent insertion or gastric-/jejunal feeding tube insertion) was needed before the start of dRCT. In the study of Bedenne et al., in patients treated with dCRT, 90.8% had problems swallowing before the start of any treatment.13 However, no data on surgical procedures performed before the start of the treatment to establish adequate nutritional pathway is reported. During dRCT all the patients were carefully monitored by attending physician and the staff of IOL’s supportive care Unit for clinical nutrition and diethotherapy, as well. In this way, we were able to select patients who needed special attention. All but one patient received either peroral or parenteral nutritional supplements during treatment and 60% of all the patients were hospitalized during dRCT for appropriate supportive treatment. Good supportive care reflects in the facts that in only 29.1% of all the patients the additional weight loss of >5% was recorded during treatment and that majority of patients could complete their treatment with the intended radiation dose to the primary tumor.

All but one patient included in the study received some sort of concomitant chemotherapy during irradiation, with 10 different chemotherapy schedules being used (see Table 2). The sort of chemotherapy used was determined by the multidisciplinary board committee’s decision taking into account the extent of the disease, patients’ general condition, comorbidities and possible synchronous tumors (8 patients with synchronous esophageal and head and neck cancers and 1 patient with synchronous esophageal and colorectal cancers). The intensity of applied chemotherapy was adjusted because of the comorbidity and/or treatment related side effects (renal impairment and/or changes in blood count) in 16.4% of patients. All others received the dose planned at the start of the treatment, which at least in part can be attributed to the good supportive care during the treatment. Majority of patients (74.5%) in our study received concomitant chemotherapy with 5-FU in continuous 96 hours infusion and cisplatin which in many countries is still the gold standard in dRCT, although according to the results of CROSS trial, nowadays many authors believe that concomitant chemotherapy with paclitaxel and carboplatin should be used in dRCT as well.6,14

In our study the total dose of 70 Gy to the primary tumor (in fractions of 2 Gy) was used in patients with tumors located exclusively in the upper third of the esophagus, whereas in patients with cervical tumors which extended in the thorax or with intrathoracic tumors, in order to avoid unacceptable toxicity, different fractionations were used with the median total dose to the primary tumor of 57.6 Gy in 32 fractions. Today, the topic of the radiation dose in dRCT is still controversial and highly debated. In the USA doses of 50-50.4 Gy are advised although many authors believe that, in order to increase the chance of better local control and survival, higher doses to the primary tumor should be used, which indeed is the case in Europe and some other parts of the world. 1,2,5,7,15

The treatment with dRCT in our group of patients was relatively well tolerated. As expected with such a treatment, in all the patients at least one treatment side effect was recorded (Table 3), with 40% of patients having at least one side effect of grade III. The most common side effects of grade III were neutropenia in 21.8% and esophagitis in 18.2% of patients, which is concordant with the data from the literature.7, 8 However, despite the treatment related side effects and because of good supportive treatment, the tolerability of the treatment in our group of patients was good, since majority of patients received the prescribed radiation dose to the tumor and in only 9 (16.4%) patients any kind of adjustments on the dose and/or number of chemotherapy applications were needed. One treatment related death was recorded at the end of dRCT in the patient in whom tracheoesophageal fistula formed on the place of esophageal stent inserted before the start of the dRCT. The problem of dose perturbations in the area of inserted metallic stents is well known.16 In our opinion, due to the relatively high radiation dose applied to the primary tumor, insertion of metallic stents before the start of the dRCT should be avoided. However, since no clinical reports on effects of stents on radiotherapy dose distribution in esophageal cancer exist, any clinical recommendations should be made with caution.

The OS in our group of patients (19.4% - see Table 4) was a bit lower if compared with the results from the literature, according to which the 5-years OS after dRCT is around 25%. On the other hand, 5-year LRC of 41% in our study, is concordant with the data from the literature with 5-year LRC after dRCT of 40-60%.3,17, 18, 19, 20 The slightly lower OS in our study can be attributed to unfavourable stage distribution since 85.5% of our patients had T3 or T4 disease and 63.6% N+ disease and the fact that of 35 patients in whom the recurrence of the disease was recorded, only 10 patients received some sort of additional specific treatment. In esophageal cancer some of the factors (such us gender, age at diagnosis, T and N stage, WHO performance stage, radiation dose received, etc.) are well recognized as the risk factors for worse treatment outcome.7,21,22 However, in our study in univariate analysis none of the analyzed factors reached statistical significance for their impact on survivals, which in our opinion can be attributed to relatively small overall number of patients and uneven distribution of patients in different subgroups tested.

Our results of treatment with definitive radio-chemotherapy in patients with esophageal cancer are concordant with the results of other studies. Due to the high intensity of existing treatment protocols, multidisciplinary approach with adequate supportive treatment is needed, and in our opinion treatment of patients with dCRT should be centralized and performed in institutions with sufficient experience and workload. Majority of our patients ended the treatment according to the protocol, which at least in part can be attributed to the adequate and well organized supportive treatment in our institution. However, the results of dRCT in general are still not satisfactory. With the increasingly widespread use of modern radiotherapy treatment techniques, such as IMRT or VMAT, there is not much room for improvement in radiotherapy part of the treatment protocols. Most probably there is still room for improvement in systemic treatment in means of intensifying chemotherapeutics given and/or with the addition of target drugs and immunotherapy, but further prospective studies addresing this subject are needed.