This phase Ⅰ/Ⅱ clinical trial determined the safety of a weekly nab-paclitaxel- and cisplatin-based regimen in cCRT in patients with locally advanced borderline-resectable or unresectable ESCC. Our study provides the first evidence that a regimen based on nab-paclitaxel and cisplatin is tolerable in cCRT for ESCC.
The newly created nab-paclitaxel has many advantages over sb-paclitaxel, such as fewer allergic reactions, no requirement for pretreatment, and a higher concentration in tumor tissue.[13, 14] With respect to first-line chemotherapy in advanced ESCC, a retrospective study demonstrated that nab-paclitaxel plus cisplatin achieved a higher objective response rate and disease control compared with sb-paclitaxel plus cisplatin.[8] In China, a regimen based on nab-paclitaxel plus platinum is used widely in ESCC as perioperative chemotherapy/radiotherapy or first-line chemotherapy. However, due to a lack of evidence-based data, a nab-paclitaxel-based chemotherapy regimen is not recommended for preoperative CRT or dCRT for esophageal cancer in CSCO guidelines.
According to the outcomes of RTOG 8501 and CROSS studies, PF and paclitaxel and carboplatin (TC) are the standard chemotherapy regimens recommended by NCCN guidelines for nCRT or dCRT of ESCC.[15, 16] In addition to PF and TC, the paclitaxel and cisplatin (TP) regimen is also standard treatment for concurrent CRT in locally advanced ESCC or first-line treatment against advanced ESCC in CSCO guidelines. Chen et al. demonstrated that the paclitaxel plus fluorouracil (TF) regimen led to similar OS with PF-based CRT against locally advanced ESCC.[17] They also showed no difference in OS among TP-, TC-, and TF-based dCRT in locally advanced ESCC, with little difference in toxicities.[18] Nowadays, paclitaxel combined with platinum-based regimens is used widely in concurrent CRT or systemic treatment of advanced esophageal cancer in China.
In the phase Ⅱ, forty-four (97.8%) patients had any grade of side-effects during cCRT, but only 11 (24.4%) patients experienced toxicities of grade ≥ 3. Radiation esophagitis was the most common toxicity of grade 3–4 (seven, 15.6%), which was comparable with other TP-based CRT studies of locally advanced ESCC (14.0–17.6%).[4, 9] Radiation pneumonia was not observed during concurrent CRT. With respect to postoperative complications, the overall prevalence in our clinical trial (61.9%) was similar to that in the nCRT group of the NEOCRTEC 5010 study (57.8%).[19] Also, the prevalence of pulmonary infection (seven, 33.3%) was similar to that observed in other studies of conversion surgery of ESCC (15.0–37.0%).[4, 20, 21] Therefore, we believe that nab-paclitaxel plus cisplatin are tolerable in terms of side-effects during radiotherapy and postoperative complications.
Locoregional recurrence after dCRT for patients with unresectable ESCC is the primary failure pattern in ~ 50% of patients, 83.3% of which occurs within 1 year and which carries a poor prognosis.[22, 23] Liao et al. compared dCRT and concurrent CRT plus surgery in stage-Ⅱ and -Ⅲ esophageal cancer.[24] They demonstrated that esophagectomy could reduce locoregional recurrence and thus lengthen OS. We obtained a 1-year LRC prevalence of 81.5% and achieved 1, 2, and 3-year OS of 86.6%, 68.8% and 57.3%, respectively, slightly better than the results of other studies of cCRT followed by surgery (3-year OS of 29.0–31.0%).[4, 25] However, due to the insufficient sample size, firm conclusions could not be drawn. Studies have shown that if patients with unresectable tumors achieved R0 resection after conversion treatment, then the survival of these patients would be lengthened significantly.[4–6, 20] Different modes of conversion therapy for patients with borderline-resectable esophageal cancer are being investigated intensely. In particular, a combination of immunotherapy, radiotherapy, and chemotherapy have made conversion therapy more diverse. Our ongoing NEXUS study reported preliminary results in 2022 ESMO-IO, indicating that conversion therapy of concurrent chemotherapy followed by immunochemotherapy achieved a prevalence of 100% for R0 resection, 61.5% for pCR, and 76.9% for the major pathologic response.
Our clinical trial had four main limitations. First, enrollment was slow and closed prematurely due to the COVID-19 pandemic. Second, we observed improvement in locoregional control and survival, but could not confirm the efficacy of the regimen because of the small study cohort. Third, this clinical trial was conducted without combination with immunotherapy, but multiple studies have demonstrated the efficacy of immunotherapy combined with chemotherapy/radiotherapy against ESCC.[26, 27] How to combine radiotherapy, chemotherapy, and immunotherapy to improve the prognosis of patients with locally advanced borderline-resectable or unresectable ESCC merits further exploration.