Radiation therapy plays an important role in the multimodality treatment of esophageal cancer. Only 30% to 40% of patients with esophageal cancer have potentially resectable disease at presentation. In combination with chemotherapy in the neoadjuvant setting, radiation has been shown to improve survival over surgery alone. Radiation also can be very effective in the palliative setting. In this chapter, we discuss the general background and data on the use of radiation in the management of esophageal cancer.

There are few studies of radiation alone for esophageal cancer, and these have generally had poor outcomes. Historically, radiation was used for patients with extensive disease or those unfit for surgery. In a review of 49 early series of patients treated with radiation alone for esophageal squamous cell carcinoma, the overall survival rate at 5 years was 6%.¹ In a British study of 101 patients with clinically localized esophageal cancer, who received definitive radiation doses of 45 to 53 Gray (Gy, unit of absorbed radiation dose), the 5-year survival rate was 21%.² In a randomized trial (Radiation Therapy Oncology Group [RTOG] 85-01) of combined chemoradiation versus radiation alone to 64 Gy for 121 patients with mostly esophageal squamous cell carcinoma, 5-year overall survival in the radiation alone arm was 0.^3,4 For this reason, radiation alone for esophageal cancer is generally considered palliative rather than curative in intent. However, there are some studies exploring whether early-stage (stage I) esophageal cancer could be effectively treated with radiation alone.⁵

Definitive concurrent chemotherapy and radiation therapy have been studied as an alternative to operative management for esophageal cancer, particularly for patients who are not good surgical candidates. RTOG 85-01 was a prospective, randomized phase III trial of patients with nondisseminated adenocarcinoma or squamous cell carcinoma of the thoracic esophagus.^3,4,6 Patients were randomized between radiation alone (64 Gy in 32 fractions over 6.5 weeks) versus concurrent chemoradiation (2 cycles of infusional 5-FU plus cisplatin and radiation [50 Gy in 25 fractions over 5 weeks]). The trial closed early because a planned interim analysis showed a significant survival advantage for chemoradiation (5-year survival 27% vs. 0%) as well as a reduction in locoregional and distant failures. However, 46% of patients in the chemoradiation arm had persistent or locally recurrent disease in the esophagus at 12 months. Severe acute but not late toxicity was significantly higher in the chemoradiation arm.

The follow-up trial to RTOG 85-01 asked the question whether radiation dose escalation may improve local control rates. In the Intergroup 0123 study (RTOG 94-05), 236 patients with nonmetastatic squamous cell carcinoma or adenocarcinoma of the thoracic esophagus received concurrent cisplatin and 5-FU, and the patients were randomized between two different radiation doses: 50.4 Gy in 28 fractions or 64.8 Gy in 36 fractions.⁷ Radiation treatment was given daily, five fractions per week. There was no significant difference in median survival (13 vs. 18 months) or locoregional failure and persistence of disease (56% vs. 52%) between the high-dose and standard-dose arms, respectively. There was also a significantly higher rate of deaths in the high-dose arm (nine vs. two events). However, of the nine treatment-related deaths in the high-dose arm, six occurred before reaching 5040 cGy, suggesting that the deaths were not related to the higher radiation dose. Nevertheless, higher radiation dose does not appear to provide a survival or local control benefit, so 5040 cGy remains the standard of care in the United States at this time.

Patients of advanced age or those with significant comorbidities may not be good candidates for surgical management of esophageal cancer. Older patients have higher rates of postoperative morbidity and mortality after esophagectomy.⁸ Studies suggest that definitive chemoradiation may be well tolerated in elderly patients, with outcomes comparable to those in younger patients.^8,9

As definitive chemoradiation in contemporary series have shown near equivalent long-term survival as surgical series, the question becomes whether patients undergoing chemoradiation for esophageal cancer benefit from surgery. The results of the 8501 study demonstrated a locoregional recurrence rate of over 45%. Although there is no clear survival benefit, studies suggest that resection leads to improved locoregional control, predominantly in squamous cell carcinoma.

In a French trial, patients with operable T2N0–1 thoracic esophageal cancer received induction chemoradiation with either protracted (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26) radiation concurrent with 5-FU/cisplatin. Patients with at least a partial response (n = 259) were randomly assigned to surgery or continued chemoradiation. At a median follow-up of 47 months, survival was not significantly different between the two groups (median survival 18 vs. 19 months), but the surgical arm had lower locoregional recurrence (34% vs. 43%, p = 0.001) and need for palliative stents.¹⁰ Quality of life was similar between the arms at 2 years.¹¹ A German trial randomized 172 patients with locally advanced esophageal squamous cell carcinoma to induction chemotherapy and chemoradiation (40 Gy) followed by surgery or the same induction regimen followed by chemoradiation (65 Gy or greater) without surgery.¹² At 5 years, overall survival was equivalent between the arms, but local progression-free survival was better in the surgery group (64% vs. 53%, p = 0.003). However, treatment-related mortality was also higher in the surgery group (12.8% vs. 3.5%, p = 0.03).

Two studies have compared definitive chemoradiation (with surgical salvage) and surgery alone for resectable thoracic esophageal squamous cell carcinoma. In a Chinese prospective randomized trial where 80 such patients received 50 to 60 Gy with concurrent 5-FU/cisplatin or esophagectomy alone, there was no difference in survival.¹³ In a similar but nonrandomized study comparing those receiving 60 Gy concurrent with 5-FU/cisplatin or surgery alone, survival rates were similar, but the surgery alone arm had a higher rate of metastases.¹⁴

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.

Preoperative Chemoradiation

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

Preoperative Chemotherapy

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 trials^24–27 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.

Meta-Analyses

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.