• Radiation therapy alone is suboptimal. In addition, there is a high rate of locally persistent/recurrent disease after chemoradiotherapy alone, and a lack of data for nonsurgical management of patients with adenocarcinoma. Thus, inclusion of surgery remains the preferred treatment approach for clinically resectable esophageal cancer.

• Contemporary series suggest that a concurrent trimodality approach (preoperative concomitant chemoradiotherapy) appears to provide a survival benefit compared to surgery alone, and is a reasonable alternative to surgery alone. This conclusion is supported by three small randomized studies , and a meta-analysis, even though the survival benefit in one of the randomized trials did not reach statistical significance, probably because it was underpowered . Further, local control appears to be better with preoperative chemoradiotherapy compared to surgery alone.

Therefore, combined modality therapy with preoperative chemoradiotherapy followed by surgery appears to be acceptable management for patients with stages IIB, III, and possibly stage IVa disease. The benefit of induction therapy for patients with early stage, localized disease (ie, stages I and IIA) is less clear so surgery alone is a reasonable option. The most recent National Patterns of Care survey noted a significant greater use of concurrent chemoradiation before planned surgery during 1996 and 1999 compared with 1992 to 1994 (27 versus 10 percent)

• Although the optimal type, dose, combination, and schedule of drugs is unclear, multiagent chemotherapy appears to be better than single agent cisplatin. We recommend preoperative concurrent treatment with two courses of cisplatin and 5-FU plus radiation therapy (50 Gy), as per the RTOG 85-01 trial. While taxane and irinotecan-containing regimens are under investigation, the results published thus far do not consistently indicate a superior toxicity profile, or higher response rates compared to standard 5-FU and cisplatin.

• Preoperative chemotherapy without radiation also provides a gain in median and two-year survival compared to surgery alone. This is the standard of care in the United Kingdom based upon the MRC trials. However, the data are insufficient to conclude that preoperative chemotherapy is preferable to preoperative chemoradiotherapy. Further, the frequency of local failure may be lower in patients treated with chemoradiotherapy followed by surgery compared to those receiving chemotherapy followed by surgery  Better control of locoregional disease by the addition of preoperative radiotherapy to chemotherapy may provide some gain in overall survival based upon the view that uncontrolled locoregional cancer is a theoretical source of ongoing distant seeding.

• Control of distant disease remains a problem with both preoperative chemotherapy and preoperative chemoradiotherapy. Both the Michigan (neoadjuvant chemoradiotherapy) and the Sloan Kettering series (neoadjuvant chemotherapy) found no difference in the rate of distant failure between the study and control arms, underscoring the need for better systemic therapies . On the other hand a response to preoperative therapy (particularly the absence of residual disease in the resected specimen) appears to be an indicator of better survival  and a reduced rate of distant metastases.

• The optimal dose-fractionation schedule of radiation for concurrent chemoradiotherapy regimens remains to be determined. However, 3-D conformal techniques should be used for modern treatment planning to minimize toxicities to adjacent vital organs (ie, heart, lung, spinal cord, or liver). The standard dose of radiation for patients treated with concurrent 5-FU and cisplatin is 50.4 Gy.

TECHNIQUE FOR PREOPERATIVE RADIATION THERAPY — The degree of response of a tumor and normal tissues/organs to radiation depends upon several radiotherapeutic factors

• Fraction size (standard fraction size, 1.8 Gy to 2.0 Gy) and interfractional intervals (standard interval, 24 hours)

• Total dose (standard preoperative dose in once daily schedule, 45 to 52 Gy)

• Duration of treatment (5 to 6 weeks for standard fractionation, without a rest during treatment)

• The arrangement of radiation portals in a manner that achieves the maximum dose differential between tumor and adjacent vital organs

Significant deviations from standard techniques should be avoided in a potentially curative setting. Fraction sizes that are larger than 2.5 Gy, treatment breaks of longer than one week, and suboptimal radiation plans with a potential for increased risk of injury to the lung, heart and spinal cord should be avoided. Three-dimensional (3-D) conformal techniques provide for optimal treatment planning.

Target volume — The target volume consists of gross tumor volume (GTV) with a surrounding margin of clinically uninvolved tissue (the clinical target volume, or CTV). The CTV should include margins of at least 5 cm beyond the radiographic tumor extent in the cephalad-caudad direction, and 2.5 to 3.0 cm beyond the lateral tumor borders (defined by barium esophagogram or CT scan). For lesions of the lower third of the esophagus and gastroesophageal junction (GEJ), the CTV is extended into the lower border of the first lumbar vertebra to include the celiac, gastric, and gastrohepatic Iymph nodes. CT of the upper abdomen is necessary to localize these lymph nodes. For lesions involving the upper two-thirds of the thoracic or the cervical esophagus, both supraclavicular regions are included in the CTV.

Optimal dose and fractionation schedules — Tumor size and radiation dose are important considerations for local control. Curative intent therapy with radiation alone requires a total dose of 60 to 66.6 Gy in 30 to 37 daily fractions of 1.8 to 2.0 Gy, administered five days per week. Small daily fractions (ie, 1.8 to 2.0 Gy instead of 2.5 to 3.0 Gy) reduce the likelihood of late toxicity.

The optimal radiation dose for preoperative chemoradiotherapy regimens is not defined, although a total dose of 45 to 50.4 Gy administered in daily 1.8 Gy fractions, 5 days per week, produces reasonable results with acceptable toxicity. Altered fractionation schedules such as accelerated schedules (45 Gy in 30 fractions over three weeks using twice daily 1.5 Gy fractions) or hybrid schedules using twice daily radiation during chemotherapy and once daily treatment between chemotherapy cycles (45 Gy in 25 fractions over five weeks to CTV, and 58.5 Gy in 34 fractions over five weeks to GTV, respectively) are tolerable, with encouraging tumor response and survival

Patients judged inoperable because of either poor general condition or the presence of distant metastases can be treated by rapid fractionation schedules. A total dose of 40 to 45 Gy at 2.5 Gy daily fractions five days a week is a reasonable schedule for patients who require palliation of malignant dysphagia.

Radiation portal arrangements — The arrangement of the radiation portals depends upon the planned total dose and region of involvement. For a two-dimensional (2-D) treatment plan, an arrangement of two parallel-opposed fields, applied anteriorly (AP) and posteriorly (PA) to the mediastinum, is simple and accurate with the least risk of a geographical miss. However, this approach needs to be combined with oblique and/or lateral portals to spare the spinal cord and heart. For cervical and upper thoracic esophageal cancer, the technique used by the author (NC) uses a sequential combination of AP-PA fields for the initial dose (36 Gy in 20 fractions over four weeks) and a three-field (AP plus oblique) arrangement for the subsequent dose (27 Gy in 15 fractions over three weeks). Radiation dose to CTV is limited to 45 Gy.

For patients with esophageal carcinoma involving the lower third of the thoracic esophagus and the GEJ, the radiation dose to the heart should be kept below the tolerance limit (ie, 40 Gy to the ventricles, especially when administered with concurrent chemotherapy). The arrangement of radiation portals used by the author includes AP-PA portals for the initial dose (30.6 Gy in 17 fractions over 3.4 weeks), and three fields (AP plus oblique) for a subsequent dose (25.2 Gy in 14 fractions over 2.8 weeks), and right lateral and left lateral parallel opposed fields for an additional dose (7.2 Gy in 4 fractions in one week), for a total dose of 63 Gy in 35 fractions over 7 weeks. The radiation dose to CTV is again limited to 45 Gy.

With the advent of 3-D conformal radiation therapy (3-D CRT) techniques, multiple portals are applied using beam's eye view for each fractional dose aiming for the maximum differential in radiation dose distribution between the target volume and normal organs. 3-D CRT plan provides a dose-volume-histogram for tumor volume as well as for normal organs at risk for complications. Thus, it is feasible to formulate radiation dose schedule for desired level of tumor control probability which is balanced with an acceptable level of toxicities.

Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D CRT. IMRT uses inverse treatment planning to generate optimum treatment plan. As a unique feature, it uses dynamic multileaf collimators to conform the radiation beam to the shape of the tumor from any angle, while protecting normal adjacent tissue as much as possible. It is expected (though not yet proven) that treatment with IMRT will result in fewer side effects

CERVICAL ESOPHAGUS TUMORS — Squamous cell cancer (SCC) of the cervical esophagus presents a unique management situation. If surgery is performed, it usually requires removal of portions of the pharynx, the larynx, the thyroid gland, and portions of the proximal esophagus. In addition, radical neck dissections are usually carried out; as such, the management is more closely related to SCC of the head and neck than for malignancies involving the more distal portions of the esophagus. Radiation combined with chemotherapy is often preferred over surgery for these patients since survival appears to be the same, and major morbidity is avoided in most.