In studies presented at the 2016 European Society for Surgical Oncology (ESMO) Congress, two different neoadjuvant treatment approaches improved the outcomes of patients with esophageal cancer.
Investigators from the Australasian Gastro-Intestinal Trials Group (AGITG) reported that the addition of docetaxel to cisplatin/fluorouracil (5-FU), especially when radiation was delivered concurrently, induced high rates of histopathologic response in patients shown to be nonresponders on metabolic positron-emission tomography (PET) imaging.1
Tailoring multimodality therapy based on individual PET response is safe and feasible in esophageal adenocarcinoma. We think this approach merits further exploration.— Andrew Barbour, MD
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Patients with esophageal cancer who do not show early metabolic responses to chemotherapy according to PET have been known to have poor survival and histologic response rates of less than 5%, the investigators noted. “We investigated if, by tailoring the neoadjuvant therapy, histologic response can be improved in patients not showing early metabolic response after the first cycle of treatment,” said Andrew Barbour, MD, of the Princess Alexandra Hospital, Brisbane, Australia.
The multicenter phase II DOCTOR study involved 124 patients with esophageal/gastroesophageal junction adenocarcinoma who received 1 cycle of cisplatin/5-FU. PET scans were performed at baseline and after one cycle of chemotherapy. If the high maximum standardized uptake value decreased by ≥ 35%, patients were classified as early metabolic responders; otherwise, they were considered to be nonmetabolic responders. The responders continued with a second cycle of cisplatin/5-FU followed by surgery. The nonresponders were randomized to receive either cisplatin/5-FU plus docetaxel (DCF) for two cycles or the same regimen concurrently with 45 Gy of radiotherapy.
There were 45 early metabolic responders and 66 nonresponders, of whom 31 were randomized to receive DCF and 35, DCF with radiotherapy. The remaining patients were not randomized due to disease progression, toxicities, or refusal.
DCF With Radiotherapy Effective, Safe
“There was not much difference between the three treatment arms in terms of need for dose modifications. We managed to deliver the dose in more than 90% of cases,” he said. “We did see some dose delays, especially among patients receiving chemoradiation, though we delivered treatment on time more than 70% of the time.”
Esophagectomy was performed on all 45 early responders (100%), on 28 of 31 patients (90%) receiving DCF (2 refused treatment; 1 experienced undue toxicity), and on 33 of 35 patients (94%) randomized to receive DCF with radiotherapy (2 progressed). Most patients (71%) were operated on via a minimally invasive approach, Dr. Barbour added.
Grade 3/4 adverse events were observed in 29% of the cisplatin/5-FU arm (mostly febrile neutropenia), 45% of the DCF arm (mostly oral mucositis), and 71% of the DCF with radiotherapy arm (mostly febrile neutropenia). “Despite this rate of adverse events, especially with DCF plus radiotherapy, we managed to get almost all patients to surgery,” he noted. There were no treatment-related deaths.
The addition of docetaxel to cisplatin/5-FU, especially with concurrent radiation, greatly improved histopathologic responses and R0 resection rates, Dr. Barbour reported.
Major histopathologic responses (< 10% residual tumor) were achieved in 21% of patients receiving DCF, 67% of those receiving DCF with radiotherapy, and 7% of the early metabolic responders. Responses corresponded with tumor downstaging and achievement of negative margins. R0 resections were possible in 64% of the DCF group, 94% of the DCF with radiotherapy group, and 69% of the early responders. There were also fewer cases of positive lymph nodes in the radiotherapy group (median 0), compared with the DCF arm (median 2) and early responder subset (median 1). Median number of nodes examined was 21, 27, and 25, respectively.
The primary endpoint was primary tumor response (ie, complete or extensive histologic response). This was achieved by 63% of the DCF with radiotherapy arm, 19% of the DCF arm, and 7% of patients with early metabolic responses, Dr. Barbour reported.
“Docetaxel added to cisplatin/5-FU, particularly with the addition of radiation therapy, increases primary tumor histologic response in metabolic nonresponders,” he stated. “DCF, especially with radiotherapy, has higher grade 3/4 adverse events than cisplatin/5-FU, but this did not prevent surgery. Tailoring multimodality therapy based on individual PET response is safe and feasible in esophageal adenocarcinoma. We think this approach merits further exploration.”
Chemoradiotherapy in Squamous Cell Carcinoma
We found that chemoradiotherapy followed by surgery could increase R0 resection rates of patients with stage IIB/III esophageal squamous cell carcinoma. It downstages the tumor significantly, achieves a high rate of pathologic complete response, is safe, and significantly prolongs overall survival.— Hong Yang, MD
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Chinese investigators also reported results for a phase III trial of neoadjuvant chemoradiotherapy, vs surgery alone, for locally advanced squamous cell carcinoma of the esophagus.2 This approach is aimed at improving outcomes for these patients, but results of different studies have been inconsistent, according to the study’s lead researcher Hong Yang, MD, of the Cancer Centre Sun Yat-Sen University, Guangzhou, China.
Dr. Yang and colleagues enrolled 451 patients with stage IIB/III squamous cell carcinoma of the thoracic esophagus to receive neoadjuvant chemotherapy and concurrent radiation followed by surgery or surgery alone. “We found that chemoradiotherapy followed by surgery could increase R0 resection rates of patients with stage IIB/III esophageal squamous cell carcinoma,” Dr. Yang said. “It downstages the tumor significantly, achieves a high rate of pathologic complete response, is safe, and significantly prolongs overall survival.”
Patients in the chemoradiotherapy arm received 2 cycles of vinorelbine and cisplatin, plus 40 Gy of radiation delivered in 20 daily fractions of 2.0 Gy each. Esophagectomy was performed 4 to 8 weeks after chemoradiotherapy. The analysis included a final population of 185 patients who underwent neoadjuvant chemoradiotherapy followed by surgery and 227 patients who underwent surgery alone.
R0 resections were achieved in 98.4% of the neoadjuvant treatment arm vs 91.2% of the surgery-alone arm (P = .002). Pathologic complete responses were observed in 43.2% of the neoadjuvant arm, and 10.8% of patients remained stage III, whereas in the surgery-alone arm, there were no (0%) R0 resections, and 62.6% of patients were stage III.
At a median follow-up of 31 months, overall survival was significantly improved after neoadjuvant chemoradiotherapy and surgery. Survival was 90.0% vs 85.8% at 1 year, 75.7% vs 72.6% at 2 years, and 69.6% vs 62.4% at 3 years (hazard ratio = 0.71; P = .035).
There were no significant differences in surgical complications, the exception being arrhythmia, which was observed in 13% of patients in the neoadjuvant arm vs 4% of those who had surgery alone (P = .001). During treatment, there were five deaths (2.2%) in the neoadjuvant arm and one death (0.4%) with surgery alone, which was not statistically significant (P = .212). ■
Disclosure: Drs. Barbour and Yang reported no potential conflicts of interest.
1. Barbour A, Walpole E, Mai GT, et al: An AGITG trial: A randomised phase II study of preoperative cisplatin, fluorouracil and docetaxel +/- radiotherapy based on poor early response to cisplatin and fluorouracil for resectable esophageal adenocarcinoma. 2016 ESMO Congress. Abstract 610O. Presented October 8, 2016.
2. Yang H, Fu J, Liu M, et al: A phase III clinical trial of neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus. 2016 ESMO Congress. Abstract 611O. Presented October 8, 2016.
No survival or relapse data are yet shown [in the AGITG trial], and the question is whether histopathologic and clinical response will translate into a survival benefit.— Florian Lordick, MD
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Florian Lordick, MD, Professor of Oncology and Director...!-->!-->