Phase I trial of hypofractionated chemoradiotherapy in the palliative management of esophageal and gastro-esophageal cancer

Abstract

Background Many patients with incurable esophageal cancer (ECa) present with dysphagia as their predominant symptom. Currently there is no consensus on how best to initially manage this scenario with multiple therapeutic options available. We aimed to assess the safety and efficacy of using hypofractionated radiotherapy given over a progressively shorter timeframe with concurrent carboplatin and paclitaxel in the management of patients with ECa and dysphagia. Methods In this phase I trial we enrolled patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction with symptomatic dysphagia from local disease and not for curative treatment. Patients needed to be 18 years or older, have an ECOG performance status of 0–2 and be suitable to receive carboplatin and paclitaxel chemotherapy. Patients were placed in four progressively shorter radiation schedules culminating in 30 Gy in 10 fractions in a step wise manner, all with concurrent carboplatin AUC 2 and paclitaxel 50 mg/m2 chemotherapy delivered weekly with the radiation therapy. The primary endpoint was the development of the dose limiting toxicities (DLTs) esophageal perforation or febrile neutropenia. Secondary endpoints were relief of dysphagia, time to improvement of dysphagia, dysphagia progression free survival and overall survival. Results Eighteen patients were enrolled in the study between October 2014 and March 2019. There were no DLTs experienced during the trial. The most common grade 3 + acute toxicity experienced by patients were nausea and vomiting (both in 4/18 patients). The most common radiation specific acute toxicity experienced was esophagitis with 67% of patients experiencing grade 1–2 symptoms. All patients experienced improvement in dysphagia. The median time to dysphagia improvement was 3 weeks from the start of chemoradiotherapy (CTRT) (range 2–10 weeks). The median dysphagia free survival was 5.8 months with a median overall survival of 8.9 months. Conclusion Hypofractionated palliative CTRT with 30 Gy/10# of radiation therapy with concurrent weekly carboplatin and paclitaxel chemotherapy is well tolerated and provides a good response in improvement of dysphagia. Further studies need to be undertaken which provide both symptomatic improvement in the primary tumor but also control of the metastatic burden in these patients. Clinical Trial Registration: This trial was prospectively registered with www.anzctr.org.au Identifier: ACTRN12614000821695.

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic oesophageal and gastrooesophageal carcinoma with dysphagia: a single arm phase II clinical trial (PALEO, sponsored by the Australasian Gastro-Intestinal Trials Group)

“…The population eligible for the PALEO clinical trial has been carefully selected as those patients most likely to benefit from combined modality therapy. The PALEO protocol delivers upfront local treatment to the primary tumour for early symptomatic and nutritional benefit, supported by our existing data shows that a 2 week chemoradiotherapy protocol (30Gy/10# with concurrent carboplatin and paclitaxel) provides rapid dysphagia relief [ 4 ]. Patients must have low volume metastatic disease (≤5 metastases, non-bulky) based on evidence that the ratio between activated T cells and tumour burden is critical for immune checkpoint inhibitor effect [ 23 , 25 , 26 ].…”

“…A phase I clinical trial conducted at our centre showed that a 30Gy in 10 fraction radiotherapy schedule given with weekly carboplatin AUC 2 and paclitaxel 50 mg/m 2 is both tolerable and highly effective in providing dysphagia relief. Among 15 patients with metastatic oesophageal cancer and three with locally advanced disease, the median time to an improvement in dysphagia was 3 weeks, and median dysphagia free survival 5.8 months [ 4 ]. This hypofractionated radiotherapy schedule is biologically equivalent to the CROSS protocol radiotherapy dose [ 5 ], while minimizing the treatment and travel burden to the patient.…”

Esophageal chemoradiotherapy with concurrent nivolumab: Pilot results in the palliative treatment of oligometastatic disease

“…4 To relieve tumor dysphagia while minimizing the treatment burden to the patient, our center previously conducted a phase 1 clinical trial of progressively hypofractionated radiotherapy with concurrent weekly carboplatin and paclitaxel, modifying the radiotherapy dose of the CROSS trial (41 Gy in 23 fractions, 4.5 weeks treatment) 5 to the biologic equivalent of 30 Gy in 10 fractions (2 weeks treatment), without any dose-limiting toxicity. 6 All patients experienced an improvement in their dysphagia after a median of 3 weeks. 6 Monoclonal antibodies to the Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis have shown efficacy in the treatment of locally advanced and metastatic disease, initially as monotherapy with response rates of 10-30% in the chemotherapy-refractory setting.…”

“…6 All patients experienced an improvement in their dysphagia after a median of 3 weeks. 6 Monoclonal antibodies to the Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis have shown efficacy in the treatment of locally advanced and metastatic disease, initially as monotherapy with response rates of 10-30% in the chemotherapy-refractory setting. [7][8][9] More recently, nivolumab and pembrolizumab have shown improved survival when administered concurrently with first-line platinum-fluoropyrimidine chemotherapy, versus chemotherapy alone.…”

“…To relieve tumor dysphagia while minimizing the treatment burden to the patient, our center previously conducted a phase 1 clinical trial of progressively hypofractionated radiotherapy with concurrent weekly carboplatin and paclitaxel, modifying the radiotherapy dose of the CROSS trial (41 Gy in 23 fractions, 4.5 weeks treatment) 5 to the biologic equivalent of 30 Gy in 10 fractions (2 weeks treatment), without any dose‐limiting toxicity 6 . All patients experienced an improvement in their dysphagia after a median of 3 weeks 6 …”