Comparison of neoadjuvant chemoradiation with carboplatin/ paclitaxel or cisplatin/ 5-fluoruracil in patients with squamous cell carcinoma of the esophagus

With 400.000 estimated deaths and 456.000 new cases in 2012 esophageal cancer (EC) is the sixth most common cause of cancer death and the eighth most common cancer in the world [1].

In 2008, Tepper et al. [2] demonstrated the superiority of neoadjuvant chemoradiation (nCRT) with cisplatin and 5-fluoruracil (CDDP/5FU) combined with subsequent surgery compared to surgery alone. Multimodal treatment was associated with a significant increase in terms of overall survival and progression-free survival and therefore nCRT with CDDP/5FU and subsequent resection became the treatment of choice for patients with locally advanced squamous cell carcinoma of the esophagus (SCC) suitable for surgery.

However, in the more recent CROSS-study, van Hagen et al. [3] compared nCRT with carboplatin and paclitaxel (Carb/TAX) and subsequent surgery to surgery alone in patients with locally advanced EC. Comparable to the results of Tepper et al. patients treated with nCRT with Carb/TAX had a significantly improved overall survival and disease-free survival compared to patients treated with surgery alone. In addition, van Hagen et al. performed a subgroup analysis for patient with SCC and adenocarcinoma (AC) of the esophagus. Thereby, the effect of nCRT was much higher for patients with SCC than for patients with AC.

At out department nCRT with CDDP/5FU was the treatment of choice for locally advanced SCC until 2014. Since then patients with locally advanced SCC were treated analogous to the CROSS-trial. Until now there is only one retrospective analysis comparing nCRT with CDDP/5FU and nCRT with Carb/TAX for patients with EC [4]. In the mentioned study, patients treated with CDDP/5FU had more hematological toxicities, whereas there was no significant difference for overall survival. However, approximately 75% of patients included in this study had AC, while only 24% of patients had SCC. Because the effect of nCRT on overall survival is  higher in patients with SCC compared to patients with AC, there might be a difference in efficiency between nCRT with CDDP/5FU and nCRT with Carb/TAX in SCC patients.

In order to clarify if there should be a preferred chemotherapy regime for SCC patients this study  evaluates and compares toxicity and oncological outcome parameters of these two different nCRT regimes in a homogenous group of SCC patients.

Between 2011 and 2016, 51 patients with locally advanced SCC were initially recruited for nCRT with either CDDP/5FU or Carb/TAX at our Department.

nCRT is the treatment of choice for patients with locally advanced SCC of the esophagus, suitable for surgery [6, 7]. Although different treatment protocols for nCRT have successfully improved overall survival and complete resection rates compared to surgery alone in EC patients, head-to-head comparisons with a competitive focus on oncologic efficacy and toxicity are still missing. The most widely used concomitant chemotherapy protocols are currently based on CDDP/5FU or Carb/TAX. In this analysis, we retrospectively compared nCRT according to the CROSS-protocol to nCRT with CDDP/5FU in a slightly modified version of the regime described by Bates et al. [8].

While there were no differences regarding overall survival and freedom from relapse for the two treatment regimes, significantly more hematologic III° toxicities were observed in patients treated with CDDP/5FU. These findings are consistent with the results of Blom et al. [4]. In their study, the authors compared nCRT analogue to the CROSS-regime with nCRT analogue to the regime published by Tepper et al. [2] for 165 patients with SCC or adenocarcinoma of the esophagus. No significant differences were seen for OS, but as in our study, patients treated with CDDP/5FU had a significantly higher risk of developing any grade III toxicity than patients treated with the CROSS-regime (41% vs. 25%). Thereby, the most common ≥ III° toxicity was leukopenia, which was observed in 24% of patients treated with CDDP/5FU and 10% of patients treated with the CROSS-regime. In our study we also recognized a significant difference regarding the incidence of ≥ III° hematologic toxicities (58% vs. 20%, ITT and 58% vs. 17%, PP). Especially for patients treated with Carb/TAX the rate of hematologic ≥ III° toxicity in general as well as the rate of anemia, leukopenia and thrombocytopenia in particular was much higher than in other studies [3, 4, 9]. Nonetheless, toxicity results for patients treated with CDDP/5FU match with the results by Tepper et al. [2] (57% vs. 58% of patients with hematologic ≥ III° toxicity) while two other studies report significant less hematologic toxicity in patients treated with cisplatin and 5-fluoruracil (15–17%) [4, 8]. However, because the difference in radiation dose between treatment groups was just 3.6 Gy our results underlines that the difference in hematologic toxicity is probably caused by the different chemotherapy regime. As in other studies leukopenia was the most common hematologic toxicity and our analysis showed a strong trend for higher grades of leukopenia in patients treated with CDDP/5FU in the ITT-analysis and significantly higher grades of leukopenia in patients treated with CDDP/5FU in the PP population.

Regarding non-hematologic side effects no significant difference was seen for the rate of insufficiencies of the anastomosis and the rate of in-hospital-mortality between both treatment regimes. However, the absolute difference in the rate of insufficiencies of the anastomosis is remarkable. While it was seen in 15% of patients who received CDDP/5FU, which is comparable to the results by Blom et al. [4] (13% vs. 15%), 33% of patients treated with Carb/TAX were diagnosed with postsurgical insufficiency of the anastomosis. These results should be kept in mind and reviewed in further trials, especially because we don’t have a convincing explanation.

In accordance with other studies no significant difference was seen for OS and FFR between both treatment groups [4, 9]. However, for patients treated with Carb/TAX median OS was significant shorter than in the CROSS-trial [3, 10]. In the CROSS-trial median OS of patients with SCC was 81.6 months. In a retrospective trial the median OS for EC patients treated with Carb/TAX was not reached after 3 years [4]. Because OS after trimodal therapy is better for patients with SCC than for patients with AC, we have to point out that in this trial only 24% of patients had SCC. For patients treated with CDDP/5FU median overall survival is comparable to other published results (17.7–53 months) [2, 4, 8, 11]. The short median OS of 17.7 months within the FFCD 9102 trial [11] (89% SCC) is probably associated with the high rate of local treatment failure (34%). Radiotherapy in this trial was done with either a conventional regime (46 Gy in 23 fractions) or as a split-course regime with 5 fractions and a daily dose of 3 Gy in the first and fourth week of treatment. In summary, the reason for the reduced median OS in patients treated according to the CROSS protocol remains unclear. However, when looking to the rate of local or distal disease progression our results show no increased incidence of treatment failure compared to the long-term data of the CROSS Trial [10]. Results for alternative chemotherapy regimens were reported in two further trials for patients undergoing definite chemoradiation for EC [12, 13]. In a phase II trial by Wolf et al. [12] 135 patients (85% SCC) received dCRT with mitomycin C and 5-fluoruracil. Radiation dose was more than 54 Gy in 85% of patients. Xia et al. [13] evaluated dCRT with weekly paclitaxel and 5-fluoruracil and simultaneous radiotherapy (50.4 Gy or 61.2 Gy) for 53 patients (94% SCC). Median OS was 15.6 months and 17.9 months, respectively. However, comparability is restricted, because patients were treated with dCRT instead of nCRT with subsequent surgery. While no further information about toxicity were given by Wolf et al. ≥ III° neutropenia was seen in 7% of patients treated with paclitaxel and 5-fluoruracil [13].

In our study complete tumor regression (pCR, Becker Ia) was seen in 28% (Carb/TAX) and 38% (CDDP/5FU) of patients, respectively. These results match with the results of the retrospective trial published by Blom et al. and van Meerten et al. [4, 14]. While these studies included patients with SCC and AC (22–24% SCC) studies focusing on only SCC patients report higher rates of pCR after nCRT with CDDP/5FU (51%) or Carb/TAX (49%) [3, 8]. This might be partially explained by the diagnostic tissue workup, because in our center we pursue a very rigorous course and pCR can only be stated when the whole tumor area has been subjected to histological workup. In accordance to the results of Blom et al., no statistically significant difference regarding the proportion of tumor regression grades was seen between both nCRT regimes [4]. An overview of different studies evaluating pCR, overall survival and hematologic toxicity of different nCRT regimes for SCC is given in Table 4.

In our study, all patients (100%) undergoing nCRT with Carb/TAX and 71% of patients treated with CDDP/5FU received radiotherapy using VMAT. This is important, because different trials have already demonstrated the superiority of VMAT over 3D–CRT for radiotherapy of esophago-gastric cancer regarding dose reduction to the organs at risk when compared to 3D–CRT [15‐17]. However, it remains questionable if these dosimetric differences alone can lead to higher rates of hematological side effects. In an analysis comparing VMAT and 3D–CRT for nCRT of esophageal cancer the use of VMAT was associated with higher rates of leukopenia when compared to 3D–CRT [16], but we have to point out that chemotherapy regime was not standardized. Therefore, the used chemotherapy regime seems to be more important for acute hematologic side effects.

Due to its retrospective nature this study has some limitations. The first problem is the relatively small number of patients in each treatment group. However, to the best of our knowledge this study includes the first dataset comparing nCRT with CDDP/5FU or Carb/TAX for patients with only SCC. Another problem is the imbalance concerning follow-up time. Because nCRT with CDDP/5FU was only used until 2014 and nCRT with Carb/TAX was only used since then, follow-up for patients treated with CDDP/5FU is obviously longer than for patient treated with Carb/PTAX, which can affect OS and FFR. Due to these limitations, the significance of the results is clearly impaired. So when looking to the fact that we could find no significant differences in terms of survival and treatment response between both groups, we have to keep in mind that the relatively small number of patients limits the power of the study.

In this retrospective analysis, no significant difference was seen for OS and FFR between nCRT with CDDP/5FU and nCRT with Carb/TAX. However, the application of CDDP/5FU was associated with significantly more hematologic III°- toxicities compared to Carb/TAX. Future prospective trials should investigate if these results are reproducible in randomized patient cohorts.