The rationale for preoperative (neoadjuvant) therapy for esophageal cancer is three-fold: to decrease micrometastases and control systemic disease, to improve resectability by tumor shrinkage, and to assess in vivo tumor response to therapy.
The use of chemotherapy concurrent with radiation preoperatively is based on the notion of radiosensitization, namely, that the chemotherapy makes radiation more effective. This treatment paradigm is also called trimodality treatment: chemotherapy and radiation preoperatively, followed by surgical resection. There are seven major randomized trials of surgery with or without preoperative chemoradiation for patients with potentially resectable esophageal cancer, three of which showed a statistically significant survival benefit for chemoradiation.
In the Irish trial by Walsh and colleagues, 113 patients with esophageal or gastroesophageal (GE) junction adenocarcinoma were randomized to surgery alone or cisplatin/5-FU–based chemoradiation before surgery.15 Chemoradiation improved survival (32% vs. 6% at 3 years), although the surgery alone arm had a lower than expected survival. CALGB 9781 randomized 56 patients with squamous cell carcinoma or adenocarcinoma of the thoracic esophagus to trimodality therapy or surgery alone. With median follow-up of 6 years, median survival was significantly improved with preoperative chemoradiation (4.5 vs. 1.8 years, p = 0.002).16 In the Dutch CROSS trial, 366 patients with potentially resectable esophageal or GE junction cancer (mostly adenocarcinoma) were randomized to preoperative chemoradiation (chemotherapy was paclitaxel and carboplatin, radiation was given to 41.4 Gy over 5 weeks) versus surgery alone. The study showed a significant overall survival benefit with preoperative chemoradiation (median survival 49 months vs. 24 months), and this 29% of patients in this arm achieved a pathologic complete response.17 There was also a higher complete (R0) resection rate in the chemoradiation-surgery group (92% vs. 69%, p <0.001).
Three other randomized trials of surgery alone versus preoperative chemoradiation followed by surgery did not show a statistically significant survival benefit to trimodality treatment.18-20 Adequate statistical power may have been an issue. As well, three studies comparing sequentially delivered chemotherapy and radiation preoperatively to surgery alone also failed to show any survival benefit to trimodality therapy.21-23
Multiple randomized phase III trials have evaluated the benefit of preoperative chemotherapy followed by surgery compared with surgery alone (no radiation in either arm). Results are mixed, with four negative trials24-27 and three showing a survival benefit to preoperative chemotherapy.28-30
Comparing Preoperative Regimens
A German study published in 2009 randomized 119 patients with locally advanced adenocarcinoma of the lower esophagus or gastric cardia to (A) induction chemotherapy (5-FU, leucovorin, cisplatin, 15 weeks) followed by surgery or (B) chemotherapy (12 weeks) followed by chemoradiation (30 Gy in 15 fractions over 3 weeks with concurrent cisplatin/etoposide) followed by surgery.31 The study closed early on account of low accrual. At a median follow-up of 46 months, the chemoradiation arm had a higher rate of pathologic complete response (16% vs. 2%, p = 0.03) and node negative disease at surgery (64% vs. 38%, p = 0.01). Three-year overall survival was 47% in the chemoradiation arm compared with 28% in the chemotherapy arm, but this did not reach statistical significance (p = 0.07). This may have been due to insufficient power.
With conflicting results from different randomized trials, we can look to meta-analyses with their increased statistical power to determine whether preoperative treatment provides a survival benefit in esophageal cancer. Sjoquist et al.32 looked at 12 trials of neoadjuvant chemoradiation versus surgery alone (n = 1854), 9 trials of neoadjuvant chemotherapy versus surgery alone (n = 1981), and 2 trials comparing neoadjuvant chemoradiation and neoadjuvant chemotherapy (n = 194), all in patients with resectable esophageal cancer. Overall, neoadjuvant chemoradiation improved survival by 22% over surgery alone. This survival benefit was seen in both adenocarcinoma (17% survival benefit) and squamous cell carcinoma (20% survival benefit). Neoadjuvant chemotherapy without radiation, compared with surgery alone, provided a 13% survival improvement. This benefit was seen in adenocarcinoma patients (17% survival benefit), but there was no significant survival benefit of neoadjuvant chemotherapy over surgery alone for squamous cell carcinoma. When chemoradiation and chemotherapy were indirectly compared, there was weak evidence favoring chemoradiation, although this was not statistically significant.
Another recently published meta-analysis found similar results.33 The authors report that neoadjuvant chemoradiation provides a 19% overall survival benefit over surgery alone, and neoadjuvant chemotherapy a 7% survival benefit. They did not find a significant increase in morbidity rates after neoadjuvant chemoradiation, and reported that the likelihood of a complete (R0) resection was 15% higher after neoadjuvant treatment. They found no significant survival difference between definitive chemoradiation and neoadjuvant treatment followed by surgery or surgery alone, although treatment-related mortality rates were over seven-fold lower.
These meta-analyses provide strong evidence for a survival benefit of neoadjuvant chemoradiation or chemotherapy over surgery alone in esophageal cancer. Although there appears to be no clear advantage of neoadjuvant chemoradiation over neoadjuvant chemotherapy, the data do suggest that chemoradiation may have a marginally greater survival benefit and higher pathologic response rate.
Measuring Response to Neoadjuvant Therapy: Implications for Individualized Treatment
Although neoadjuvant therapy followed by surgery has emerged as the standard of care for locally advanced esophageal cancer, there is variability in response to neoadjuvant treatment. Some patients may have a complete response but will go on to resection and be exposed to the risks of surgery. Similarly, for patients who do not respond to neoadjuvant chemotherapy, their prognosis after this treatment might be worse than that of a primary surgical approach, especially if there was local disease progression.
A German phase II trial (MUNICON) used FDG-positron emission tomography (PET) imaging to identify early responders to neoadjuvant chemotherapy.34 Patients (n = 119) with locally advanced adenocarcinoma of the distal esophagus or gastric cardia had a baseline PET scan, then went on to receive 2 weeks of 5-FU/platinum-based induction chemotherapy. Those with a decrease of 35% or more in tumor glucose standard uptake value (SUV) on repeat PET were defined as metabolic responders and went on to receive 12 more weeks of chemotherapy and then surgery. Patients who did not have a sufficient response on PET to the 2 weeks of induction chemotherapy were considered nonresponders and went straight to surgical resection. Median event-free survival was higher among PET responders (30 months vs. 15 months, p = 0.002), and these patients were also more likely to have an R0 resection and complete pathologic response at surgery.
A follow-up study, MUNICON II, treated nonresponders to induction chemotherapy with salvage neoadjuvant chemoradiation before surgery.35 With this salvage treatment, nonresponders had an improved histopathologic response rate when compared with the MUNICON I results. A recent retrospective study showed that PET complete response predicted improved survival after definitive chemoradiation, but not after trimodality therapy for esophageal cancer (neoadjuvant chemoradiation + surgery).36 These preliminary data suggest that FDG-PET may help to identify patients in whom surgery might be avoided, but would need to be tested in a prospective study. The goal of identifying responders to neoadjuvant treatment is to potentially tailor therapies based on tumor biology and response.