Breast cases.

In the past years we saw many new studies in local treatment of breast cancer.

First case. 55 year old woman with a 1.5 grade 2 IDC ER+ HER2 neg, no LVI, she has a lumpectomy, SN biopsy, she has AD. In total she has 3 out of 18 positive nodes. The recurrence score is 15. For adjuvant systemic therapy the options are AC, TC, ACT, HT alone.

83% would do ACT followed by HT. 

I which ER positive patient I get an oncotype. I think that oncotype is a reasonable test to get. If there is not a choice to be made about ChT there is no reason to get an oncotype. This is a pt who would have been eligible for the old SWOG trial that looked at CAF plus T versus T. In that trial in a retrospective analysis oncotype was predictive of the benefit of ChT. Many people are less comfortable moving forward with a no ChT approach because the absolute benefit is larger. That said 15 is a pretty low score. In the clinical trial we redefine what is a low oncotype score like in the tailor X study where no or low ChT score was 10 or under. 18 or under is a low oncotype score. In both retrospective studies it was associated with no or minimal benefit from ChT.

I think in this situation you can make a reasonable argument to differ ChT and HT. You can make argument to give ChT alone. IN a trial pats with node positive disease are randomized to receive HT alone or HT plus ChT. That trial includes pts who has an oncotype score between 0 and 25. I would have a conversation with these pts. 

The other issue is that if you decide to give this pt ChT the question is if ChT followed by HT is the appropriate regimen. Pts who have a low oncotype score do pretty well. BC specific mortality for pts for pts with low oncotype score after AC or ACT was 2%. The question is do you need a long regimen. The benefit of taxanes is minimum to none. We could not show an interaction of treatment effect. The HR for recurrent is 1. So essentially no benefit. Probably no benefit from any ChT.

One of the problems wth the SWOG retrospective study is that it is predictive in not giving a benefit from ChT but the risk was pretty high. It has a high risk with HT alone. 

MA 20 I believe it is still a review. The journal asked for updated results. This study was presented 3 years ago at ASCO. 1800 pts 85% had 1 - 3 positive nodes. They were treated with lumpectomy and WBI plus or minus nodal irradiation including intramammary nodes. There was a benefit in loco regional control. The rate of mets at 5 years was low (32% reduction). OS was almost significant. 

The EORTC trial is going to be reported out the next couple of weeks. It is also a positive trial. These 2 studies will have a huge impact in terms of our treatments. 

Let us go back to this pt. Low recurrence score. In terms of irradiation do you do breast tangents, high tangents, tangents and SC and axillary apex, tangents SC and IMN.

In the absence of publications 38% would do breast tangents, 41% would do tangents and SC axillary apex, only 16% would include the IMN. 

I would do breast tangents. 

I would do breast tangents alone. Number 2 is a wrong answer as it targets only the LN that have been dissected. Number 4 would be my second choice. It is a very heterogenous group. MA 20 has influenced us. The probability of having microscopic disease in IMN is high. 

Regional recurrence in pts who had ChT is very low, 2 - 3%. You published a paper on oncotype and loco regional recurrence. 

Second case. It is a 55 year old pt. This pt has LVI. She has 2 of 15 positive nodes both has macro mets. She got ChT and HT. What would you do regarding radiation, tangents, high tangents, tangents + SC + apex of axilla, tangents and full nodal irradiation. It was a grade 3. 

36% tangents, 15% would include IMN. It is in the grey zone. I would have a discussion with the pt. 

I would treat as number 4. She is borderline. 

The improvement in survival with RT is also in the pts with 1 - 3 positive nodes. In pts with 1 - 3 positive nodes you have to do a full dissection. The use of post mastectomy RT has a 10 year gain in recurrence, 15 year gain in mortality. The benefit was similar with 1 positive node, 2 positive nodes and 3 positive nodes.

In this study there is a reduction in recurrence but the mortality benefit is considerably less. 

Third case. 48 pre menopausal women 1.8 cm cancer. Grade 2.  No LVI. She underwent mastectomy. SN node followed by AND, 1 positive node. Macromet. Would you do no radiation, tangents, tangents and SC, tangents and full nodal irradiation. 

14% would do no radiation, 44 tangents and superclav, 30% tangents apex and IMN. 

I would pick one. It is a very favourable case similar to the first case. 

We started to treat with SC about 25% of people with 1 - 3 positive nodes. In the 75% which did not do SC the recurrence rate was less than 5%. 

This pt has a small disease burden. The danish trial is still driving a meta analysis. 

When you consider 1 - 3 positive LN the risk of recurrence is quite low. 

I would pick number 1. 

I would do number 1 as well. We can only look at the results of randomized trials. 

In the more moderns data sets you see lower recurrence rates. We are starting to see a survival benefit. 

Many people would not benefit from ChT. Most of these data are old data. 

General Management

Treatment for esophageal carcinoma is characterized as curative or palliative. According to one historical study,⁹⁵ only 20% patients present with cancer of the esophagus that is truly localized to the esophagus, indicating that at the time of diagnosis, approximately 80% patients have either locally advanced or distant disease.

Surgery with Curative Intent

Surgery of the thoracic esophagus usually requires a subtotal or total esophagectomy and is usually undertaken for lesions of the middle to lower one-third of the thoracic esophagus and gastroesophageal junction. Patients with stage I to III are often considered for potentially curative resection; however, aortic, tracheal, heart, or great vessel invasion may preclude resection. Esophagectomy may be accomplished by a number of techniques, including a transhiatal esophagectomy, right thoracotomy with laparotomy with intrathoracic anastomosis (Ivor-Lewis esophagogastrectomy), right thoracotomy with laparotomy with cervical anastomosis (McKeown esophagogastrectomy), left thoracotomy, or radical esophagectomy via open or laparoscopic approaches. Each technique has its advantages and disadvantages. In general, advantages of the transthoracic approach include better visualization with access and resection of the upper two-thirds of the esophagus and mediastinal lymph nodes. Alternatively, the transhiatal approach has less morbidity than thoracotomy (including respiratory compromise) with easier access to anastomotic leaks (neck vs. thorax). In any instance, achievement of negative margins at resection has been reported to be a significant prognostic factor and should be the goal of esophageal resection. Exemplifying this, in a study of 500 patients undergoing transthoracic resection, patients undergoing margin-negative resection had a 5-year survival rate of 29% versus no 5-year survivors in patients with involved margins.⁹⁶

The Ivor-Lewis procedure is the classic approach to expose mid-esophageal lesions. A left thoracotomy procedure exposes lesions of the gastroesophageal junction. Transhiatal esophagectomy is performed without a thoracotomy and is useful in lower esophageal lesions, although direct visualization and dissection of varying mediastinal lymph nodes cannot be achieved. The optimal surgical approach is unknown. A randomized trial comparing transhiatal versus transthoracic approaches in patients with adenocarcinoma showed no significant survival advantage to the latter, although a possible trend was noted (5-year survival, 29% vs. 39%). However, perioperative mortality was also increased with the transthoracic approach.⁴⁶

Laparotomy can be performed before or concurrently with esophagectomy to rule out any disease below the diaphragm. Multiple reconstruction options are available following definitive surgery; esophagogastrostomy is the most widely used, using the stomach as a conduit to replace the esophagus. Patients with significant obstruction and inability to maintain their weight often require placement of feeding jejunostomy. If possible surgery is planned, gastric tube placement is generally avoided, given that the stomach will ultimately serve as the “neoesophagus” following resection. Colon interposition, preferably with the left colon, can also be used; however, this approach is generally reserved for patients who have previously undergone gastric surgery or other procedures that have devascularized the stomach.

Squamous cell carcinoma of the cervical esophagus presents a difficult management situation. Proximal esophageal tumors <5 cm from the cricopharyngeus are generally treated with definitive chemoradiotherapy. If surgery is performed, resection of portions of the pharynx, the entire larynx, thyroid gland, and the proximal esophagus is often required. Radical neck dissections are also carried out.⁵⁰ Because of the significant morbidity and loss of organ function with surgery, chemoradiation alone has been frequently employed. The survival probability with definitive chemoradiotherapy is similar, without the major functional impairments, morbidity, and mortality associated with surgery.⁹⁷

Curative Combination Therapy

In the treatment of patients with esophageal cancer, an approach of radiation therapy with concurrent chemotherapy, with or without surgery, is frequently adopted. Multiagent chemotherapy with cisplatin and 5-fluorouracil (5-FU) is used most frequently, although combinations of other agents (e.g., paclitaxel and carboplatin) are being increasingly used. Additional taxanes, topoisomerase inhibitors, and anti-epidermal growth factor receptor inhibitors with radiation therapy are under investigation.

Palliative Treatment

Palliative treatment is frequently used for the relief of symptoms of esophageal carcinoma, especially dysphagia.⁹⁸ Surgical palliation involves resection and reconstruction, if possible, removing the bulk of the disease, potentially preventing abscess and fistula formation, as well as bleeding. Substernal bypass with the colon or entire stomach has also been carried out.⁹⁸ However, given the poor prognosis in patients with advanced disease and morbidity associated with resection, a surgical approach is not commonly adopted and should be avoided in patients who can be managed with nonsurgical modalities.

Endoscopic dilatation is a reasonable alternative. When the lumen of the esophagus is dilated to 15 mm, dysphagia is often no longer experienced. Repeat dilatation is often required.⁵⁰ Esophageal stenting with either conventional plastic stents or metallic self-expanding stents can also be used to maintain patency.⁹⁹

Palliative irradiation is frequently used to control the primary disease, as well as distant metastases. Resolution of symptoms, especially pain and dysphagia, can be accomplished in up to 80% of patients. Palliative treatment regimens range from 30 Gy over 2 weeks⁵¹ to 50 Gy over 5 weeks. Laser ablation with or without intraluminal brachytherapy can be used. The addition of 3 fractions of 7 Gy each can improve the stenosis-free interval and prevent obstruction.⁹⁹

Radiation Therapy Techniques

Simulation

When patients are simulated, the radiation oncologist should know the extent of disease based on imaging (barium swallow, CT, PET), as well as on endoscopy. CT simulation is appropriate for treatment planning. During simulation, the patient is positioned, straightened, and immobilized on the simulation table. An immobilization device is used to minimize variation in daily setup. Arms are generally placed overhead and knee support underneath the legs. Palpable neck disease should be marked with a radiopaque wire. The administration of oral contrast to delineate the esophagus is generally used and helps to define the extent of mucosal irregularity. For GE junctional tumors (particularly with significant gastric involvement), it may be advisable to have the patient come in with an empty stomach. For cervical and upper thoracic lesions, an immobilization mask may assist in creating a reproducible position. Some authors have also advocated that mid-esophageal primaries be simulated in prone position to maximize distance between the target volumes and spinal cord. The patient is placed on the CT simulator in the treatment position, and a scan of the entire area of interest with margin is obtained. At minimum, 3- to 5-mm slices should be used, allowing accurate tumor characterization, as well as improved quality of digitally reconstructed radiographs. If patients lose >10% of their body weight during therapy, consideration should be given to repeat CT planning. Arterial phase intravenous contrast is generally used to delineate mediastinal and abdominal vascular nodal basins, including the celiac axis and to allow the radiation oncologist to discern normal vasculature from other adjacent normal structures, and potential adenopathy. The tumor and vital structures are then outlined on each slice on the treatment planning system, enabling a three-dimensional treatment plan to be generated. The use of respiratory gating or breath-hold techniques may help to reduce target motion with respiration and, therefore, avoid normal-tissue irradiation associated with larger margins used in free-breathing approaches, particularly for lower esophageal cancers. Additional techniques to minimize physiologic motion include abdominal compression devices. Four-dimensional CT scan may be appropriate to assess tumoral motion, facilitating appropriate margin placement on the target volumes, particularly in lower esophageal tumors and/or disease involving the stomach.

Treatment Planning

Target Design

In the design of radiation fields for esophageal cancer, it is important to define varying target volumes, including gross disease as well as potential areas of subclinical involvement (i.e., the gross tumor volumes [GTVs] and clinical target volumes [CTVs], respectively). Definition of gross tumor volume is based on multiple studies, including endoscopic descriptions (from both esophagogastroduodenoscopy [EGD] and EUS). The proximal and distal aspects of the tumor should be standardly defined by the gastroenterologist based on distance from the incisors, as well as relationship to varying landmarks as measured from the incisors (e.g., the GE junction). The radiation oncologist is able to use these measurements to help correlate with disease extent visualized on planning CT scan, using varying anatomic landmarks (e.g., the GE junction, which is frequently located ~40 cm from the incisors in many patients), as well as carina (which is frequently located at ~25 cm in most patients) to help more accurately define the GTV. Esophageal wall thickening correlating to the gross tumor volume can frequently be visualized on diagnostic and radiation planning CT. Similarly, EUS appears to be the most reliable test in detecting lymphadenopathy related to nodal spread. As in EGD, the endoscopist should be encouraged to accurately define not only the primary disease extent on EUS as measured by distances from the incisors, but also depth of penetration and potential involvement of adjacent structures, which can also be used to help guide GTV delineation. Similarly, EUS may detect lymph nodes that may not be appreciated on CT or PET imaging, and the endoscopist should describe the size as well as the location (e.g., distance from incisors, relationship to adjacent mediastinal structures, etc.) of these, further facilitating accurate definition of potentially involved lymph nodes, either adjacent to or well removed from the primary tumor itself. In addition, radiographic areas of lymphadenopathy should similarly be included in the GTV.

Although the utility of PET in esophageal cancer staging primarily lies in its ability to detect distant metastases not fully appreciated on CT imaging (and thereby alter treatment approach of these patients),^100,101diagnostic PET/CT has more recently been integrated into radiation planning of esophageal cancer patients and definition of GTV. Generally, gross disease as defined on PET is characterized by a standard uptake value of >2 to 2.5.¹⁰² Generally speaking, PET-avid nodes should be included within the GTV volume. In a study from Fox Chase Cancer Center, the mean GTV length as determined by PET/CT closely correlated with endoscopy findings.⁵⁹ Another study from Australian investigators reported that CT-alone–based definition of GTV excluded PET-avid disease in a majority of patients, resulting in a potential geographic miss of disease in a significant minority of patients.¹⁰³ Similarly, the fusion of CT-PET has been shown to prompt GTV and planning target volume (PTV) modification in a majority of patients.¹⁰⁴ Recent analysis of PET/CT-based (as compared to CT alone) radiotherapy planning of esophageal cancer patients indicated a reduction of intraobserver and interobserver variability in GTV delineation.¹⁰⁵

Finally, although the routine use of fluoroscopic barium swallow in esophageal cancer has decreased, this study may still be useful to the radiation oncologist for field design. A study by Chinese investigators suggested that, as compared to CT, endoscopy with barium swallow more accurately defines the true length of middle and lower esophageal tumors, although CT appeared to better determine this for tumors located at the GE junction.¹⁰⁶

In summary, accurate definition of primary and nodal gross disease is paramount in radiation esophageal cancer planning. It is important to rely on all diagnostic studies, including barium swallow (when available), EGD, EUS, and CT, as well as PET scan.

The identification of potential direct and nodal pathways for spread of subclinical disease (i.e., CTV definition) in esophageal cancer is also of paramount importance. These areas vary significantly, depending on site of origin of disease, making esophageal cancer planning somewhat complex. In terms of direct disease extension along the esophagus itself, varying reports have assessed the histologic findings at primary esophagectomy to determine subclinical extent of disease. One prospective analysis of 66 resection specimens showed that placement of a 3-cm margin proximally and distally on the primary tumor would cover microscopic disease extension in 94% of squamous cell carcinomas. Similarly, in GE junctional carcinomas, a 3-cm proximal margin included subclinical disease extension in 100% of patients, and 5 cm distally covered 94% of subclinical spread.¹⁰⁶

As described previously, the esophagus is characterized by a rich submucosal network of lymphatics that facilitates early lymph node spread of disease, even for superficial esophageal cancers. The appropriate cranial and caudal margins remain a matter of debate in the treatment of esophageal cancer. Historically, very large fields were treated, encompassing potential pathways and lymphatic spread from the thoracic inlet down to the celiac axis region; however, such fields are potentially fraught with treatment-related toxicity and may be difficult for patients to tolerate, particularly in the context of concurrent chemotherapy delivery. Most contemporary radiation trials used margins of 3 to 5 cm cranially and caudally on the GTV, along with an approximate 2-cm radial margin. With disease located at or above the carina (or middle/upper one-third of the esophagus in some instances), many of these trials recommended fields inclusive of the supraclavicular lymph node basins, whereas celiac axis nodal basin coverage was recommended for disease of the distal esophagus.¹⁰⁷ Further description of lymph node basin coverage follows.

Field Design

Historically, the treatment of very proximal (cervical) esophageal cancers has been challenging. Because of the changing contour from the neck to the thoracic inlet, treatment of lesions in the upper one-third of the esophagus may present a difficult technical problem. Lesions in the upper cervical or postcricoid esophagus are treated from the laryngopharynx to the carina, depending on extent of disease. Supraclavicular and superior mediastinal nodes are irradiated electively. Using older/conventional methods, this was achieved with lateral parallel opposed or oblique portals to the primary tumor and a single anterior field for the supraclavicular and superior mediastinal nodes.⁹³ Another historical technique treated lesions in this region by means of a four-field box approach, using a wax bolus to build up the lack of tissue above the shoulders, acting as a compensator. A high-energy beam (>15 MV) is used, and both sides of the neck are treated prophylactically. Other methods of treating lesions at the thoracic inlet include 140-degree arc rotations, anterior wedged pairs, and three- or four-field techniques using posterior oblique portals combined with a single anterior portal or anteroposterior–posteroanterior (AP/PA) fields.⁹³ Using three-dimensional (3D) approaches, varying techniques have been implemented, including treatment of the primary tumor and lymph nodes using an AP/PA approach to 39.6 to 41.4 Gy at 1.8 Gy per fraction, followed by a left or right opposed oblique pair to bring the total dose to 50.4 Gy, thereby limiting the spinal cord dose. This technique will generally exclude the supraclavicular fossa, and a separate electron field is often added, treating to a depth of 2 to 3 cm, depending upon individual anatomy. More recently, however, intensity-modulated radiation therapy (IMRT)–based planning has facilitated the treatment of upper esophageal lesions and is our preferred method for treating these tumors (Fig. 53.9) Strict normal tissue constraints, including normal lung and spinal cord, are important considerations in using these techniques (discussed later).

FIGURE 53.9.

A–C: Examples of planning target volume (PTV) in a 62-year-old woman with a cT3 N1 squamous cell carcinoma of cervical esophagus. Gross tumor volume (GTV), blue volume; PTV, red volume. D: Three-dimensional reconstruction of PTV from above the patient. Carina, yellow; GTV, dark blue; lungs, light blue; PTV, red; spinal cord, brown. E: Isodose curves of this patient treated with a nine-field intensity-modulated radiation therapy plan. Note that beams are primarily anteriorly oriented.

Based on the previously described and other pathologic patterns of spread data in squamous cell carcinoma of the esophagus, general guidelines in terms of field design can be made as follows: For cervical and upper thoracic squamous cell carcinoma, the CTV should generally include nodal basins extending from the lower cervical and supraclavicular region superiorly to the subcarinal lymph node basin inferiorly, inclusive of the upper paraesophageal lymph nodes (Fig. 53.9). For lower esophageal squamous cell carcinomas, lymph node basins from the subcarinal region superiorly to the left gastric and common hepatic artery/celiac lymph nodal basins inferiorly should generally be included (described further later in this chapter). For tumors of the middle esophagus, we recommend individual field design according to clinical scenarios, with a more complete coverage of paraesophageal mediastinal lymph nodes, particularly in patients with a good performance status (Fig. 53.10).³⁷ These are general guidelines, and all plans should be individualized based on available imaging and endoscopic findings.

FIGURE 53.10. Example field for a midesophageal squamous cell carcinoma.

Note that the field is inclusive of adjacent mediastinal/paraesophageal nodes, with approximately 5 cm margin superiorly on the gross tumor volume (GTV), as well as slightly larger margin on the inferior aspect of the GTV based on concern of previously unappreciated spread at time of endoscopy.

In field design, potential nodal involvement (and therefore target volumes) on nodal size is problematic, given that some reports demonstrated that <15% of metastatic nodes are >1 cm and that average size differences between involved and uninvolved nodes are frequently not significantly different.¹⁰⁸ In addition, fluorodeoxyglucose-PET scanning has an estimated sensitivity of only 67% of detecting nodal metastases.⁸Even endoscopic ultrasound, generally considered the most sensitive test for detecting lymph node metastases, is only able to detect such disease in approximately 75% of patients.¹⁰⁹ Therefore, it is not appropriate to rely exclusively on varying imaging modalities to define areas of subclinical spread for esophageal cancer, realizing that patterns-of-spread data are important in determining radiation field design.

The design of radiation fields for the treatment of adenocarcinoma of the esophagus is similar to that of lower thoracic squamous cell carcinomas but deserves special mention. Periesophageal lymph nodes are generally included in all patients. Given that lymph node involvement is clearly associated with depth of tumor penetration (T stage) and the fact that most patients in the United States and Europe presenting with GE junctional carcinoma will have more advanced disease, inclusion of celiac lymph basins for adenocarcinoma of the distal esophagus/GE junction is usually indicated. Based on the previously described patterns of spread data from Erlangen and others, specific considerations include the following: Lymph vascular invasion is highly predictive of nodal spread. Proximal extension of tumors (particularly beyond the Z-line into the distal esophagus for type II and III tumors) predicts an increasing incidence of paraesophageal lymph node involvement. Based on an estimated nodal incidence cutoff of 20% for inclusion, specific considerations include the following: (a) The lower paraesophageal, paracardial, lesser curvature, and left gastric artery nodes should be included in the CTV. (b) The presence of lymph vascular invasion predicts a nodal positivity rate of >20% in the left and right gastroepiploic, greater curvature, celiac trunk, and splenic hilar regions. (c) In T3/4 disease, the gastroepiploic, greater curvature, celiac trunk, splenic hilar, splenic artery, and common hepatic artery should be included. (d) High-grade tumors should also include the left gastroepiploic, greater curvature, and celiac trunk nodes in CT design. (e) Larger and more deeply penetrating tumors should also include the splenic artery and splenic hilar nodes, as well as those along the greater curvature. (f) Tumors extending above the diaphragm and those extending >1.5 cm beyond the Z-line should include the mid paraesophageal nodes, treating up to the carina. Of note, significant involvement of the distal esophagus by GE junctional tumors (>1.5 cm beyond the Z-line) should lead to inclusion of not only lower, but also middle paraesophageal nodes based on patterns of spread. However, treating these more extensive fields must be weighed against potential side effects of increased normal-tissue irradiation. In summary, middle and lower paraesophageal nodes should be included in patients with T2-T4 type I and T2-T4 type II tumors extending >1.5 cm above the Z-line and T3-T4 type II patients. The splenic hilar and artery nodes are considered “spareable” in T2 tumors, notably type I.⁴²

Although, historically, two-dimensional–based radiation planning has been carried out primarily using anatomic landmarks such as bone and carina, as well as fluoroscopic barium swallow, to determine field borders, contemporary treatment planning using CT-based planning allows improved visualization of both target and nontarget structures, along with three-dimensional reconstruction and creation of a “beam's-eye” view of varying fields, allowing improved conformality around target structures and improvements in normal-tissue sparing. Because volumetric data can be obtained by CT scans, dose–volume histogram data can also be generated. A variety of three-dimensional techniques are being used and are described later.

Potential beam orientations for the treatment of thoracic esophageal and gastroesophageal junction tumors (again defined as tumors involving the gastroesophageal junction with an epicenter within 5 cm proximal or distal to the GE junction) include an AP/PA-alone approach, an initial AP/PA approach followed by AP/right posterior oblique (RPO)/left posterior oblique (LPO) fields with or without boost, an initial APPA approach followed by RAO/LPO fields with or without boost, and a three-field technique (AP/PA with left lateral or oblique field). One of our preferred approaches in lesions of the thoracic esophagus or GE junction is to use an initial AP/PA/RAO/LPO fields, with boost fields using laterally oriented beams. The inferior margin of the initial fields includes the gastroesophageal junction and, for lower or middle one-third lesions, the celiac axis nodal basins (generally located at the level of T12 and identifiable on CT), as well as gastrohepatic ligament. Initial fields are treated to a dose of 45 Gy, taking care to avoid as much of the heart as reasonably possible while continuing to minimize the kidney volume in the radiation field, inclusive of the above nodal basins. Reduced fields encompassing gross disease with an approximate 2-cm margin through oblique or lateral fields may then be used for an additional 5.4 Gy. Doses usually do not exceed 50 Gy (discussed later).

A margin of 5 cm above and below the GTV is generally recommended to cover subclinical submucosal/nodal disease, as well as an approximate 2.0- to 2.5-cm radial margin, although individual margins are case dependent. Because it is imperative to account for daily setup uncertainty as well as physiologic internal organ motion (secondary to respiration, peristalsis, cardiac motion, etc.), additional margin must be added to a clinical target volume, particularly to the more mobile distal esophagus. More recently, the internal target volume (ITV) has been used to account for physiologic motion of the target volume, which is included in the PTV. Varying reports analyzing esophageal motion have shown average anterior and posterior motion ranges from 0.1 to 4 mm, lateral motion from 0.3 to 4.2 mm, and superior-to-inferior motion from 3.7 to 10 mm.¹⁰⁷An analysis evaluating interfraction esophageal motion in the right–left and AP direction showed average right–left motion of 1.8 ± 5.1 mm (favoring leftward movement) and average AP motion of 0.6 ± 4.8 mm (favoring posterior movement), with an average absolute motion of 4.2 mm or less in the right–left and AP directions. The authors concluded that 12-mm left, 10-mm posterior, and 9-mm anterior margins are appropriate.¹¹⁰ Some authors have recommended defining 1-cm radial, 1.5-cm distal, and 1-cm proximal margins from CTV to ITV if target motion data are not available. Image-guided radiation therapy, including cone beam CT, may also be useful in localizing tumor and establishing physiologic variability between daily treatments.

Figure 53.11 shows general recommendations for elective target nodal station coverage in a patient with a type I GE junctional tumor with an accompanying example field. Figure 53.12 shows general recommendations for elective target nodal station coverage in a patient with a type II GE junctional tumor. Nodal basins are similar to type I tumors with the exception of inclusion of nodal basins along the splenic artery course. Figure 53.13 shows general recommendations for elective target nodal station coverage in a patient with a type III GE junctional tumor with accompanying example fields. Note that in type III tumors there is less emphasis on more proximal (lower mediastinal) nodes and more comprehensive coverage of the splenic artery course, including splenic hilum. Figure 53.14 shows examples of varying nodal locations on axial CT images.

FIGURE 53.11.

A: Recommended nodal basins to be included for type I gastroesophageal (GE) junctional tumors based on Japanese Gastric Cancer Association lymph node stations. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009;92:164–175; with permission from Elsevier.) B: Example field for a type I GE junctional adenocarcinoma. C: Example oblique field for a type I GE junctional tumor, inclusive of the above nodal basins.

FIGURE 53.12. Recommended nodal basins to be included for type II gastroesophageal junctional tumors based on Japanese Gastric Cancer Association lymph node stations.

FIGURE 53.13.

A: Recommended nodal basins to be included for type III gastroesophageal (GE) junctional tumors based on Japanese Gastric Cancer Association lymph node stations. (From Matzinger O, Gerber E, Bernstein Z, et al. EORTC-ROG expert opinion: radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach. Radiother Oncol 2009;92:164–175; with permission from Elsevier.) B: Example field for a type III gastroesophageal junctional adenocarcinoma. C: Example oblique field for a type III GE junctional tumor, inclusive of the above nodal basins.

FIGURE 53.14. Examples of lymph node stations on corresponding computed tomography slices.

Another potential approach in the treatment of thoracic esophageal cancer is the use of IMRT. IMRT also uses CT-based planning, again allowing 3D reconstruction of varying structures. However, IMRT differs from 3D planning through the delivery of radiation dose by partitioning a radiation field into multiple smaller fields of varying shapes and sizes, varying the dose intensity between each area. This is carried out with either dynamic IMRT (in which collimating leaves move in and out of the radiation beam path during treatment) or “step-and-shoot” IMRT (in which the leaves change the radiation field shape while the beam is turned off). Either method is particularly effective at conforming radiation dose to the target structures while avoiding dose to normal tissue. Radiation oncologists must determine which structures are most critical and weight their importance during the treatment planning process. Of importance, the greater the number of “avoidance” normal structures, the more difficult it is to meet all dose constraints. IMRT use “inverse planning,” in which an intended prescription dose is placed on target volumes and dose constraints are placed on normal-tissue structures. Thereafter, computer software algorithms allow design of unconventional treatment fields that would not otherwise be possible with standard planning methods. Radiation oncologists and medical physicists critically evaluate numerous plans until dose constraints are satisfactorily met. The result should be a series of radiation doses that closely conform to the target volumes while minimizing dose to normal tissues. Dosimetric comparisons of IMRT versus 3D conformal therapy in cervical esophageal cancer have demonstrated superior target volume coverage and conformality with decreased normal-tissue dose.¹¹¹A potential disadvantage of IMRT is the possibility of delivering low doses of radiation therapy to normal tissue areas that might not normally be irradiated using 2D or 3D techniques. The influence of this on toxicity (e.g., low-dose pulmonary irradiation and development of postoperative pulmonary complications) remains uncertain. Another potential disadvantage to IMRT is possible dose inhomogeneity, leading to potential hot spots in normal organs. Because IMRT requires precise target definition, the potential for marginal miss increases, and careful target delineation is of paramount importance. With setup uncertainty, physiologic organ motion, and so on, care must be taken to ensure accurate and reproducible setup, including the use of immobilization devices, possible respiratory gating/breath-hold techniques, and so on. Generally, high-energy photons (4 to 18 MV) are recommended when using 3D conformal or IMRT therapy, potentially facilitating a reduction the integral lung dose.

Dose Constraints

In radiation therapy planning of esophageal cancer, normal-tissue tolerance should always be considered. The spinal cord dose is generally limited to 45 Gy using 1.8-Gy fractions (and potentially less when delivered with novel systemic agents). Efforts to minimize radiation to the heart (in particular the left ventricle in lower esophageal/gastroesophageal junction lesions) should be made. Adopting an off-heart approach using oblique orientations (including right anterior and left posterior, described earlier) is one potential way of achieving this, although multiple approaches exist, including IMRT-based techniques. Similarly, efforts to minimize dose to normal pulmonary tissues should be made, based on data suggesting that the volume of irradiated lung may correspond to postoperative complications and worsened pulmonary function (described later). Frequently, the volume of irradiated lung can be minimized using a simple AP/PA approach. However, this sometimes results in significant cardiac dose, particularly in lower esophagus and gastroesophageal junction tumors. Therefore, oblique orientations are sometimes used, resulting in increased volumes of normal lung being irradiated. When giving concurrent chemotherapy, we generally limit these fields to 13 to 15 Gy.

Accurate delineation of adjacent organs, including lungs, liver, kidneys, heart, and spinal cord, is important. Varying dose–volume normal-organ constraints have been suggested, including achieving a lung V₂₀ of <20%, limiting >2,300 cc of normal lung tissue to <5 Gy, and using mean lung dose of <18 Gy. Similarly, aV₁₀ of ≤60% has been proposed to reduce the incidence of postoperative pulmonary complications. Historically, heart dose constraints have included maintaining one-third, two-thirds, and total heart volumes of <45, 40, and 30 Gy, respectively. Recommended heart constraints include keeping <30% of the cardiac volume to a total dose of 40 Gy and <50% receiving 25 Gy, minimizing dose to the left ventricle. In the setting of potentially significant volumes of heart in the radiation field, consideration of 4D CT and/or breath-hold techniques can be made. For lower esophageal and gastroesophageal cancers, it is recommended that at least 70% of one physiologically functioning kidney receive a total dose of <20 Gy, and that, collectively, no more than 50% of the combined functional renal volume should receive >20 Gy.⁴¹ One should also consider the possibility of impaired kidney function in the context of varying comorbidities, using nuclear medicine renal studies to assess individual renal function in such situations or where significant volumes of kidneys are anticipated to be within the radiation field. Generally, 70% of the liver parenchyma should be kept to a dose of <30 Gy. Many of these constraints can be achieved through the use of three-dimensional planning with appropriate and careful design of shielding blocks/multileaf collimation and dose-volume histogram analysis, with the use of IMRT in select cases.

Doses of Radiation

Because local-regional failure is common after conventional chemoradiation, investigators have evaluated dose escalation techniques. Varying series using doses beyond 50 Gy have shown local control rates ranging from approximately 77% to 88%.^112,113 However, Minsky et al.^114,115 reported the results of a randomized trial in which 236 patients with clinical stage T1-4, N0/1, M0 squamous cell or adenocarcinoma of the esophagus were selected for nonsurgical therapy. Patients were randomized to receive 64.8 versus 50.4 Gy, both with concurrent 5-fluorouracil and cisplatin chemotherapy. Patients with cervical, mid, or distal esophageal cancer were eligible, with the exception of those with tumors within 2 cm of the gastroesophageal junction, with approximately 85% of patients with squamous cell histology. This study was closed after interim analysis showed no probability of superiority in the high-dose arm. No significant difference in median survival (13 vs. 18.1 months), 2-year survival (31% vs. 40%), or local-regional failure/persistence of disease (56% vs. 52%) was seen between the high-dose and standard-dose arms. Eleven treatment-related deaths occurred in the high-dose arm compared with 2 in the standard-dose arm, with 7 of the 11 high-dose arm deaths occurring in patients who received 50.4 Gy or less. The authors performed a separate survival analysis including only patients receiving the assigned radiation dose. Despite this, no survival advantage was noted in the high-dose arm. These authors concluded that higher radiation doses did not increase survival or local/regional control, and that the standard radiation dose for patients treated with concurrent 5-FU and cisplatin chemotherapy is 50.4 Gy. Based on these data, standard dose of radiation therapy for esophageal cancer is usually 50 to 50.4 Gy at 1.8 to 2 Gy per fraction, including delivery of similar doses in the both the definitive, adjuvant (45 to 50 Gy) or neoadjuvant (45 to 50 Gy) settings.

Brachytherapy

In addition to external-beam radiation therapy (EBRT), intracavitary therapy can be used with curative or palliative intent. Brachytherapy has also been used as a dose escalation tool in addition to EBRT. The advantage of brachytherapy centers on exploitation of the inverse-square law and quick dose fall-off, thus sparing surrounding tissues from radiation while providing focal dose escalation. The radioactive source of choice is usually ¹⁹²Ir. High–dose-rate (HDR) techniques can deliver 100 to 400 Gy/hour, allowing treatment to be given in 5 to 10 minutes.

With brachytherapy, an afterloading catheter is introduced through the nose into the esophagus to the primary tumor site under fluoroscopic guidance. This is often performed with the patient on the simulation table. Contrast may be used to define the tumor site. CT scan can also be used to discern tumor location. After localization films are taken and dosimetry generated, the catheter is then attached to a remote afterloader through a guide cable and the ¹⁹²Ir source inserted through remote control. Doses of 5 to 20 Gy are usually delivered to a depth of 1 cm from the center of the catheter. Dose can be shaped and modified through the use of dwell times.

Results of Therapy

The best survival results have been reported in patients who have esophageal tumors that are truly localized. Survival rates range from 25% to >35% at 5 years, and these results have been attained using an array of treatment approaches. Problems arise in comparisons of various modalities, however, because of patient selection factors. A review of the Princess Margaret Hospital data¹¹⁶ supported the concept that extent of tumor, rather than therapy, is the most important factor influencing survival. They found a significant correlation between T stage and response to treatment: T1 lesions showed a 100% response rate, whereas T2 and T3 lesions had response rates of 68% and 58%, respectively. Not unexpectedly, they also found differences in survival according to T stage, M stage, and overall stage. Almost 20% of patients with stage I disease were alive at 3.5 years, whereas only 11% of stage II patients were alive after the same interval, and all patients with stage III died of disease by approximately 1.5 years following therapy.

Surgery Alone

Surgery remains a benchmark to which other modalities are compared. Surgery removes the tumor, a length of normal esophagus, and lymph nodes. Although multiple techniques exist for the resection of esophageal cancer, no one surgical approach has clearly been shown to be superior with regard to complications or outcomes. Proponents of more extended resection (including transthoracic approaches) have advocated that such procedures result in a superior nodal clearance and therefore offer a more complete “oncologic” resection. A trial from the Netherlands randomized 220 patients with esophageal adenocarcinoma to transhiatal esophagectomy alone or transthoracic esophagectomy with extended lymph node dissection. Patients undergoing transhiatal resection experienced significantly fewer pulmonary complications and chylous leaks, as well as significantly reduced ventilator dependence and intensive care unit and hospital stays. At a median 4.7-year follow-up, no significant difference in local-regional recurrence was seen between the two groups (32% transhiatal vs. 31% transthoracic). Furthermore, no significant differences were seen in median disease-free survival (1.4 vs. 1.7 years; p = .15) or median overall survival (1.8 vs. 2.0 years; p = .38). However, there did appear to be a nonsignificant trend favoring the transthoracic approach in improved disease-free survival (5-year, 27% vs. 39%) and overall survival (5-year, 29% vs. 39%) The authors concluded that a transhiatal approach was associated with less morbidity relative to transthoracic surgery, with no apparent survival advantage with either technique, although a trend toward improved survival with longer follow-up was seen.⁴⁶ In summary, none of the surgical approaches to localized esophageal cancer has clearly been shown to be superior with regard to complications or outcomes, and no one standard surgical approach exists for esophageal cancer resection.

After resection alone, however, local-regional relapse is a common mode of failure. Contemporary randomized trials with surgery alone arms have reported local regional failure rates of 32% to 45%.^46–49 It should be remembered that patterns of failure reports often describe first site of failure only and may include only patients undergoing R0 resection, potentially underreporting the true incidence of local-regional recurrence. These and other data suggest that even with modern surgical techniques, local-regional persistence of disease after resection remains a major problem. Prospective, randomized trials using surgery alone in the treatment of esophageal cancer have reported 3-year survival rates ranging from 6% to 48%, with more favorable rates likely reflecting inclusion of patients with earlier-stage disease^117–121 (Table 53.7). Given these high rates of relapse and poor long-term survival, the integration of adjuvant or neoadjuvant chemoradiation approaches into the treatment of esophageal cancer is rational and indicated.

TABLE 53.7. Comparison of Surgical Arms in Randomized Studies

Radiation Therapy Alone

There are no randomized studies comparing surgery alone with radiation alone, and radiation therapy alone has been usually delivered when lesions are deemed inoperable because of tumor extent, medical contraindications, and/or palliative treatment is indicated. In general, patients receiving radiation as a sole treatment modality have a median survival of 6 to 12 months and 5-year survival of <10%.

A large review analyzing 49 series involving >8,400 patients treated primarily with radiation therapy alone found overall survival rates at 1, 2, and 5 years to be 18%, 8%, and 6%, respectively.¹²² Hancock and Glatstein⁹⁷ reviewed 9,511 patients and found only 5.8% were alive at 5 years. Okawa et al.¹²³ reported 5-year survival rates by stage. For patients with stage I disease, the 5-year survival rate was 20%; stage II, 10%; stage III, 3%; and stage IV, 0%. Overall, the 5-year survival rate was 9%. For cervical esophageal lesions treated with radiation alone, the cure rates are comparable with those in patients treated with surgery alone. Lederman¹²⁴ treated 263 patients with radiation therapy alone and reported 3- and 5-year survival rates of 11% and 7%, respectively. In a more contemporary series, an Intergroup randomized study (discussed later) comparing combined chemotherapy with 5-FU and cisplatin with radiotherapy (50 Gy) versus radiotherapy only (64 Gy) showed that 3-year survival with radiotherapy alone was 0%. These and other data suggest that treatment with radiation therapy alone for esophageal cancer patients is palliative in the vast majority of patients.

Preoperative Radiation Therapy

The use of preoperative radiation therapy has potential biologic and physical advantages, including increased resectability of tumors, increased tumor radioresponsiveness secondary to improved tumor oxygenation, a theoretical decreased likelihood of dissemination at the time of surgery, and avoidance of surgery in patients with rapidly progressive disease.

There are multiple, largely historical randomized studies comparing preoperative irradiation followed by surgery with surgery alone. These studies demonstrate no clinical benefit to the use of preoperative radiation therapy alone (Table 53.8). Launois et al.¹²⁵ reported delivering 40 Gy over 8 to 12 days with surgery 8 days later versus surgery alone. Resection rates were similar—70% and 58% for preoperative irradiation and for surgery alone, respectively. The 5-year survival rate after resection was 11.5% for those treated with surgery alone, compared with 9.5% for those treated with irradiation and surgery. The second randomized study, published by the European Organisation for Research and Treatment of Cancer (EORTC), used 33 Gy over 12 days.¹²⁶There was no significant difference in survival between those receiving preoperative irradiation and those receiving surgery alone. Arnott et al.¹²⁷ reported on 176 patients, 86 of whom were treated with esophagectomy alone versus 90 who were treated with preoperative radiation therapy. Preoperative radiation therapy was delivered with 4-MV photons using opposed fields, delivering 20 Gy at 2 Gy per fraction. Resectability and local failure were not reported. Patients receiving low-dose radiation therapy did not demonstrate a benefit in 5-year overall survival rates (17% vs. 9% for surgery and preoperative radiation, respectively; p = .4). Wang et al.¹²⁸ randomized 206 patients to surgery alone versus 40 Gy in 2-Gy fractions delivered preoperatively. No significant survival advantage was seen for patients receiving radiation therapy (35% vs. 30%; p > .05).

TABLE 53.8. Randomized Trials of Preoperative Radiation Therapy for Esophageal Cancer

A meta-analysis from the Oeosophageal Cancer Collaborative Group updated data from five randomized trials of >1,100 patients comparing preoperative radiotherapy alone versus surgery alone. The majority of patients had squamous cell carcinoma. At a median follow-up of 9 years, the hazard ratio was 0.89, suggestive of an overall reduction in the risk of death of 11% and absolute survival benefit of 4% at 5 years with the use of preoperative radiotherapy. However, this was not statistically significant (p = .06). The authors concluded that there was no clear evidence that preoperative radiotherapy improves survival of patients with potentially resectable esophageal cancer.⁴

In general, there were no differences in resectability rates or survival in almost all of the individual studies. Interpretation of these varying studies is complicated by differences in radiation techniques, suboptimal radiation doses, and inadequate radiation volumes. Nonetheless, although preoperative radiation therapy alone may improve local control, there is no convincing data that it results in improved survival in esophageal cancer patients.

Postoperative Radiation Therapy

The main advantage to adjuvant versus neoadjuvant approaches is knowledge of the pathologic staging for appropriately selected patients for therapy. Postoperative therapy may allow the radiation oncologist to treat areas at risk for recurrence while sparing otherwise normal radiosensitive structures, thereby decreasing toxicity. In addition, patients with pathologic T1, N0, M0 or metastatic disease may be spared treatment. Postoperative irradiation has historically been delivered to patients with esophageal cancer who have bulky tumors with gross residual disease or histologically proven microscopic residual disease. Potential disadvantages of postoperative radiation include limited tolerance of normal tissues after gastric pull-up or intestinal interposition and irradiation of a devascularized tumor bed, potentially larger fields compared to a preoperative approach, and potential delays in adjuvant treatment delivery.

Three randomized trials have assessed surgery alone versus surgery followed by postoperative radiation therapy.^129–131 In a French trial, 221 patients with squamous cell carcinoma of the mid-lower esophagus undergoing esophagectomy were randomized to postoperative radiation therapy or no further treatment. Patients were stratified by extent of nodal involvement. Total dose was 45 to 55 Gy at 1.8 Gy per fraction, beginning within 3 months of surgery. Five-year survival in node-negative patients was 38% versus 7% with involved nodes. No significant survival difference was seen in patients receiving postoperative radiation versus surgery alone. Rates of local regional recurrence were lower in patients receiving radiation therapy (85% vs. 70%; p = NS). However, in patients without nodal involvement, local-regional recurrence was significantly improved in patients receiving postoperative therapy (90% vs. 65%; p < .2). The authors concluded that postoperative radiation therapy did not improve survival after resection for squamous cell carcinoma.¹²⁹

Investigators from the University of Hong Kong reported the results of a randomized trial of 130 patients treated with postoperative radiation therapy versus surgery alone. Patients who underwent either curative or palliative resections were included in this trial. Radiation therapy was delivered to a total dose of 49 Gy (curative patients) or 52.5 Gy (palliative patients) using 3.5-Gy fractions. Most patients had squamous cell histology. Local recurrence was noted in 15% of patients receiving radiation and 31% of patients with surgery only (p = .06). In patients with squamous cell carcinoma, the local recurrence rate was 15% with radiation therapy versus 36% with surgery alone (p = .02). Median survival in patients was worse in patients receiving postoperative radiotherapy versus control patients (8.7 vs. 15.2 months; p = .02). Ten patients undergoing surgery alone had tracheal bronchial recurrence resulting in death versus 3 patients receiving adjuvant radiation therapy (p = .07). The authors concluded that postoperative radiation therapy was associated with increased morbidity and death caused by irradiation injury, as well as with the early appearance of metastatic disease and a reduced overall survival, although patients receiving radiation therapy were less likely to have a tracheobronchial recurrence. However, it should be noted the high rate of complications associated with radiation therapy in this study may possibly be related to the high dose per fraction and large total dose delivered.¹³⁰

Last, a study conducted by Xiao et al.¹³¹ randomized 549 patients to radical resection versus radical resection followed by radiation therapy. All patients had squamous cell carcinoma. The radiation dose delivered was 60 Gy in 6 weeks. Patients were classified into three groups: group 1, no lymph node involvement; group 2, one to two lymph nodes involved; group 3, three or more lymph nodes involved. Results showed T stage, stage group, and the number of lymph nodes involved by tumor were highly predictive of survival. The 5-year survival for groups 1, 2, and 3 were 58.1%, 30.6%, and 14.4%, respectively. Local control and survival were improved in patients receiving postoperative irradiation. For patients with involved lymph nodes, 5-year survival for resection-only patients versus patients receiving resection and radiation therapy were 17.6% and 34.1%, respectively (p = .04).

In summary, postoperative radiation therapy may decrease local recurrence, particularly in the setting of involved margins, although the impact of this adjuvant treatment on overall survival remains less clear.

Postoperative Combined Chemoradiation

A large randomized Intergroup trial evaluating the role of adjuvant chemoradiation after surgery versus surgery alone for patients with adenocarcinoma of the stomach and GE junction was reported. In this study, patients with resected, margin-negative gastric or gastroesophageal junction adenocarcinoma were randomly assigned to surgery alone versus surgery with postoperative chemoradiotherapy. Approximately 20% of patients had lesions in the gastroesophageal junction. A significant survival advantage was seen in the adjuvantly treated group (median survival 27 vs. 36 months; p = .005). On subset analysis, this benefit was detected in patients with gastroesophageal cancer.¹³² Long-term results at >10-year median follow-up continued to show significant improvement in overall and disease-free survival in the chemoradiation group, benefiting all T- and N-stage patients included in the trial.¹³³ Therefore, in patients with resected-stage group Ib-IV, nonmetastatic GE junctional carcinoma, it is appropriate to advise adjuvant chemoradiotherapy in efforts to potentially improve upon local control and survival.

Preoperative Chemotherapy

Five randomized trials showed conflicting results with the use of neoadjuvant chemotherapy alone in the treatment of esophageal cancer, with two of these trials also including gastric cancers. Kelsen et al.⁴⁷ reported the results of an Intergroup study randomizing 440 patients with squamous cell carcinoma and adenocarcinoma to receive either combined cisplatin or 5-FU chemotherapy for three cycles followed by resection, followed by a similar regimen of adjuvant chemotherapy, versus immediate resection with no chemotherapy. No apparent survival advantage (3-year survival of 23% vs. 26%) was seen in patients receiving chemotherapy. In addition, rates of local failure (32% vs. 31%) and distant metastasis development (41% vs. 50%) were not significantly different between the two groups. The authors concluded that neoadjuvant chemotherapy with cisplatin and 5-FU did not improve survival in patients with resectable esophageal cancer. Long-term results from a follow up analysis reported that only 59% and 63% of patients undergoing preoperative chemotherapy and surgery alone, respectively, underwent R0 resection, and patients undergoing less than R0 resection had an ominous prognosis, with only 5% of patients undergoing R1 resection surviving >5 years and no difference in median survival rates for patients with R1, R2, or no resection. In this follow-up study, patients with objective tumor regression after preoperative chemotherapy did have improved survival. An important caveat from this study is that all long-term R1 survivors received adjuvant RT, and the authors concluded that after R1 resection, postoperative chemoradiotherapy offers the possibility of long-term disease-free survival to a small percentage of patients.¹³⁴

In contrast to the Intergroup study, a similar trial from the Medical Research Council (MRC) randomized 802 patients with squamous cell carcinoma or adenocarcinoma of the esophagus to either two cycles of combined cisplatin/5-FU chemotherapy or surgery alone. Patients receiving neoadjuvant chemotherapy had a statistically improved 2-year survival (43% vs. 34%).¹¹⁸ Follow-up analysis at a median follow-up of 6 years showed a persistent, significant survival benefit in the chemotherapy group (5-year survival 23% vs. 17%), with the effect maintained for both squamous cell carcinoma and adenocarcinoma patients.¹³⁵ The reason for outcomes differences between these trials is not clear.

A smaller trial of 169 patients with squamous cell carcinoma of the esophagus randomized patients to receive preoperative chemotherapy alone with two to four cycles of etoposide and cisplatin–based chemotherapy versus surgery alone. Median and 5-year survival rates significantly favored the chemotherapy group at 16 versus 12 months and 26 versus 17%, respectively. The authors concluded that preoperative chemotherapy with a combination of etoposide and cisplatin improves survival in patients with squamous carcinoma of the esophagus.¹³⁶

A more heterogeneous European study (the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial) randomly assigned patients with resectable adenocarcinoma of the stomach, gastroesophageal junction, or lower esophagus to preoperative and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU versus surgery alone. Although originally designed to include patients with only tumors of the stomach, eligibility was later expanded to include tumors of the lower one-third of the esophagus. Approximately one-fourth of patients had adenocarcinoma involving the lower esophagus or gastroesophageal junction. No patient achieved pathologic complete response. However, patients receiving perioperative chemotherapy had a hazard ratio for death of 0.75, which was highly significant. Five-year survival in patients receiving chemotherapy was 36% versus 23% in patients undergoing surgery alone (p = .009). Subgroup analysis of patients with lower esophageal or gastroesophageal junction tumors showed benefit to the delivery of perioperative chemotherapy.¹³⁷ A follow-up study is evaluating the role of the vascular endothelial growth factor inhibitor bevacizumab with a similar backbone regimen.

French investigators reported the results of a similar randomized trial of 224 patients assigned to perioperative chemotherapy (cisplatin and 5-FU) versus surgery alone. Although originally designed to include only patients with tumors of the lower one-third of the esophagus or gastroesophageal junction, eligibility was later expanded to include gastric cancers. Most patients (75%) had disease of the lower esophagus or gastroesophageal junction. Chemotherapy consisted of planned two or three preoperative and three or four postoperative cycles. This study was prematurely terminated because of low accrual. Patients receiving chemotherapy had improved overall survival (5-year, 38% vs. 24%; p = .02), disease-free survival (5-year, 34% vs. 19%, p = .003), and R0 resection rates (84% vs. 73%; p = .04). Only 50% of patients received postoperative chemotherapy. T0 disease (complete pathologic response at the primary site) was seen in 3% of neoadjuvantly treated patients. Total local regional recurrence rates were 24% and 26%, respectively in the chemotherapy versus surgery group, with distant recurrence rates of 42% versus 56%, respectively.¹³⁸ In addition to the foregoing studies, two recent meta-analyses suggested that neoadjuvant chemotherapy resulted in absolute 2- and 5-year survival benefit of 7% and 4%, respectively.^139,140

Preoperative Chemoradiation versus Surgery Alone

Walsh et al.¹¹⁷ reported a randomized study to evaluate the role of concurrent preoperative chemoradiation combined with surgery. A total of 110 patients with adenocarcinoma of the esophagus were randomized to receive cisplatin, 5-FU, and concurrent radiation therapy followed by surgery versus surgery alone. Combined-modality patients received two courses of chemotherapy at weeks 1 and 6. Patients were treated using anteroposterior–posteroanterior fields (later changed to a three-field technique) to a total dose of 4,000 cGy in 15 fractions. Surgery was performed 4 to 6 weeks later, using five separate approaches. Median survival was 16 months with preoperative chemoradiation therapy compared to 11 months for the patients treated with surgery alone (p = .01). The 1-, 2-, and 3-year survival rates were 52%, 37%, and 32%, respectively, for patients who received multimodality therapy and 44%, 26%, and 6%, respectively, for those patients assigned to surgery. These results were significant at 3 years (p = .01). The authors concluded that neoadjuvant chemoradiation was superior to surgery alone in patients with resectable esophageal adenocarcinoma. This trial has been criticized for its poor surgery-alone results, short follow-up, and lack of prerandomization CT staging.

Urba et al.⁴⁹ reported the results of 100 patients with nonmetastatic esophageal carcinoma (squamous and adenocarcinoma histology) randomized to receive preoperative chemoradiation followed by surgery versus transhiatal esophagectomy alone. Chemotherapy consisted of cisplatin, 5-FU, and vinblastine. Only 69% of the patients were able to receive the intended chemotherapy dose. Radiation was delivered at 1.5 Gy twice daily for 3 weeks to a total dose of 4,500 cGy. No elective nodal irradiation was performed. Surgery was performed on day 42. Tumors >5 cm, patient age >70 years, and squamous cell histology were associated with inferior survival. At median follow-up of 8 years, no significant difference in survival was seen between treatment arms, with a median survival of 17 months. However, 3-year survival rate was 16% in the surgery-alone arm versus 30% in the combined-modality arm (p = .15). A higher incidence of locoregional failure as first site of failure was seen in surgery-alone patients (42% vs. 19%, p = .02). In patients experiencing pathologic complete response, a median survival of 50 months and a 3-year survival rate of 64% was seen versus patients with residual tumor in the surgical specimen, where median survival was 12 months with a 3-year survival rate of 19% (p = .01). The investigators stated that “Although this is not statistically significant, this suggests a possible trend to the benefit of multimodality therapy, but the sample size was too small to detect a more subtle survival difference,” and that surgery should be continued as a standard of care.

Bosset et al.¹¹⁹ reported an EORTC trial randomizing 282 patients with squamous cell carcinoma of the esophagus to either immediate surgical resection or preoperative therapy using concurrent cisplatin chemotherapy with radiation therapy. Patients were treated with split-course radiotherapy with a 2-week interval, using 3.7 Gy per fraction to a total of 37 Gy. Postoperative mortality was significantly higher in patients receiving preoperative therapy (12% vs. 4%). Outcomes showed patients receiving neoadjuvant therapy experienced a significant improvement in disease-free survival, cancer-related mortality, margin-negative resection, and local control; however, no improvement in overall survival was seen versus patients undergoing surgery alone (median survival was 18.6 months for both groups). The authors concluded that neoadjuvant chemoradiation improved disease-free survival and local control in patients with squamous cell carcinoma of the esophagus but had no impact on overall survival. They judged that the increase in postoperative mortality in the combined group “could be due to deleterious effects of the high-dose of radiation per fraction,” among other factors, and believed that the dose of 3.7 Gy per fraction “probably had a detrimental effect.” This trial has also been criticized for the split-course treatment approach, as well as for potential delivery of suboptimal chemotherapy.

Burmeister et al.¹⁴¹ reported an Australian study randomizing 257 patients with adenocarcinoma and squamous cell carcinoma of the esophagus to surgery alone versus neoadjuvant therapy using concomitant 5-FU and cisplatin. Patient received 2.33 Gy per fraction to a total dose of 35 Gy. Patients undergoing neoadjuvant therapy had a 16% pathologic complete response rate at resection. Patients receiving neoadjuvant therapy were more likely to undergo curative resection and have negative lymph nodes on histologic examination. However, no significant improvement in median survival was seen (19 vs. 22 months; hazard ratio 0.89; p = .57). On subset analysis, there appeared to be a trend toward improved survival in patients with squamous cell carcinoma undergoing neoadjuvant therapy versus surgery alone (progression-free survival hazard ratio, 0.47; p = .01; overall survival hazard ratio, 0.69; p = .16). The authors concluded that neoadjuvant chemoradiation as delivered in their study provided no obvious survival benefit in patients with esophageal cancer, although further study was warranted in patients with squamous cell carcinoma. Potential criticisms of this trial include delivery of a single chemotherapy cycle, as well as delivery of lower radiation doses.

Results of a Cancer and Leukemia Group B study described 56 patients (75% with adenocarcinoma) randomized to either surgery alone or neoadjuvant chemoradiation followed by surgical resection. Patients in the neoadjuvant therapy arm received cisplatin/5-FU–based chemotherapy and 50.4 Gy of external beam radiation therapy at 1.8 Gy per fraction. This trial was closed prematurely due to poor accrual. In patients undergoing neoadjuvant therapy, pathologic complete response rate was 40%. A significant improvement in local control and survival was seen in patients receiving neoadjuvant combined-modality therapy (5-year survival, 39% vs. 16%). The authors concluded that neoadjuvant chemoradiation in patients with esophageal cancer significantly improves progression-free and overall survival.¹⁴²

Results of the largest randomized trial (the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study, or CROSS trial) assessing neoadjuvant chemoradiotherapy in the treatment of esophageal cancer showed a significant survival benefit in patients receiving preoperative therapy, with the majority of patients included in this trial having locally advanced adenocarcinoma.¹²⁰ Patients with resectable T1N1 or T2-3 N0-1 tumors received preoperative chemoradiotherapy consisting of weekly paclitaxel and carboplatin with concurrent radiotherapy to a dose of 41.4 Gy versus surgery alone. R0 resection rates were 92% in patients receiving neoadjuvant chemoradiotherapy versus 69% for surgery alone, with a pathologic complete response rate of 29% in patients receiving preoperative therapy. No significant differences were seen in in-hospital mortality (4% vs. 4%). Median survival was 49 months in patients receiving chemoradiotherapy versus 24 months in surgery alone, with a significant improvement in 3-year survival (58% vs. 44%). The authors concluded that weekly administration of carboplatin and paclitaxel with concurrent radiotherapy improves overall survival compared to surgery alone and that this regimen can be considered the standard of care for patients with resectable esophageal or esophagogastric junction cancer.

In contrast, a preliminary report from France evaluating primarily early-stage squamous cell esophageal cancer patients randomized to receive preoperative chemoradiotherapy versus surgery alone showed no significant difference in outcomes.¹²¹ In this study, patients with early-stage disease (stage I-II) were randomized to receive surgery alone versus neoadjuvant chemoradiotherapy using concurrent 5-FU and cisplatin with 45 Gy. Thirty-day postoperative mortality rates were 1% in the surgery-alone group versus 7% in the neoadjuvant group (p = .054). Median survival was not significantly different between the groups (44 vs. 32 months; p = .66). The authors concluded that neoadjuvant chemoradiotherapy with cisplatin and 5-FU did not improve survival but increased postoperative mortality for patients with early-stage esophageal cancer. Outcomes of these trials are shown in Table 53.9.

TABLE 53.9. Results of Preoperative Combined Chemoradiation versus Surgery Alone—Phase III Trials

Given these conflicting results of contemporary trials, multiple meta-analyses have been performed. Two of the largest and most contemporary of these demonstrated an absolute 2- and 5-year overall survival benefit of 13% and 6.5% with the use of neoadjuvant chemoradiotherapy, respectively, when compared to surgery-alone approaches, also suggesting a larger benefit of preoperative chemoradiotherapy as compared to a chemotherapy alone.^139,140 It should be kept in mind that some of the included trials used sequential (vs. concurrent) chemotherapy, delivered what would be considered suboptimal doses of radiation therapy, used antiquated radiation therapy techniques, delivered (arguably) inadequate chemotherapy, and so on, potentially underestimating the effect of neoadjuvant combined-modality therapy. That being said, an updated meta-analysis including a total of 24 randomized trials evaluating the role of neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, or comparison of the two in patients with resectable esophageal cancer was recently reported,¹⁴³ evaluating the outcomes of >4,000 patients. All-cause mortality for neoadjuvant chemoradiotherapy trials estimated an absolute survival benefit at 2 years of 8.7%, with survival benefits similar between squamous cell carcinoma and adenocarcinoma patients. By comparison, estimated absolute survival difference at 2 years was 5.1% in patients receiving neoadjuvant chemotherapy and was significant only for adenocarcinoma patients. The authors concluded that neoadjuvant chemoradiotherapy improves survival compared with surgery alone in operable patients, as does neoadjuvant chemotherapy, although the benefit of neoadjuvant chemotherapy was not as great as with neoadjuvant chemoradiotherapy, that a clear advantage is not established, and further randomized trials comparing these two strategies are warranted.

In summary, the above data suggest that neoadjuvant concurrent chemoradiation improves local control and modestly improves survival versus surgery alone in patients with resected esophageal cancer.

Preoperative Chemoradiation versus Preoperative Chemotherapy

A randomized trial comparing neoadjuvant chemotherapy alone versus neoadjuvant combined-modality therapy was conducted by German investigators (Preoperative Chemotherapy, or Radiochemotherapy in Esophagogastric Adenocarcinoma, or POET, Trial).¹⁴⁴ Patients with advanced esophagogastric adenocarcinoma were randomized to receive (a) cisplatin/5-FU–based chemotherapy alone versus (b) a similar induction chemotherapy, followed by concurrent cisplatin/etoposide with 30 Gy of radiation therapy. Both groups went on to receive surgery. Although this study was closed early due to poor accrual, patients receiving preoperative chemoradiotherapy had significantly higher N0 rates (37% vs. 64%; p = .04) and pathologic complete response rates (2% vs. 16%; p = .03), as well as significant trends toward improved local control (59% vs. 76%; p = .06) and overall survival (3-year survival, 28% vs. 47%; p = .07; hazard ratio, .67). The authors concluded that preoperative combined modality improves overall survival as compared to chemotherapy alone in patients with locally advanced esophagogastric adenocarcinoma.

A smaller phase II study from Australian investigators randomized 75 patients to receive either preoperative chemotherapy with cisplatin and infusional 5-FU versus preoperative chemoradiotherapy with the same drugs with radiation therapy commencing day 21 of chemotherapy, delivering 35 Gy in 15 fractions.¹⁴⁵Histopathologic response rate and noncurative resection rates were significantly improved in the radiation-containing arm (8% vs. 31% and 11% vs. 0%, respectively). However, median overall survival was not significantly different between the groups (29 vs. 32 months). The authors concluded that despite their being no difference in survival, the potential advantage of achieving negative margins made preoperative chemoradiotherapy a reasonable option for bulky, locally advanced resectable adenocarcinoma of the esophagus.

Radiation Therapy Alone versus Chemoradiation

There are multiple randomized studies comparing radiation therapy alone with concurrent radiation and chemotherapy^146–148 as definitive therapy. However, many of these studies are handicapped by small patient numbers, substandard chemotherapy delivery, and the use of suboptimal radiotherapy techniques. This makes treatment results difficult to interpret. The landmark trial establishing the superiority of concurrent chemoradiation to radiation therapy alone was Radiation Therapy Oncology Group (RTOG) 85-01. Herskovic et al.¹⁴⁹ reported results of this two-arm trial that treated 60 control patients with radiation alone to a total dose of 64 Gy versus 61 patients with 50 Gy of radiation therapy with concurrent 5-FU and cisplatin. The chemotherapy protocol consisted of four planned courses of infusional 5-FU and cisplatin. Although less radiation was delivered in the concurrent-therapy arm, the results demonstrated a significant advantage of the combined-modality arm over the radiation-alone arm. The median survival in patients treated by radiation alone was 8.9 months compared with 12.5 months for those treated with combined therapy, with 2-year survival rate 10% versus 38%; the incidence of local recurrence decreased from 24% to 16%, and the 2-year distant metastasis rate decreased from 26% to 12%. Because of this highly significant survival difference, the randomization was stopped, and 69 additional patients were treated on the chemoradiation arm. Updated trial results^146,150 showed that at 5 years, survival rates were 26% and 0%, respectively, for chemoradiation and radiation therapy alone. Local recurrence rates were also decreased with the use of combined-modality therapy versus radiation alone (45% vs. 69%), and distant metastases were more frequent in the radiation-alone arm at 40% versus 12% for the combined-modality group. The incidence of acute toxicity, however, was higher for the combined-modality arm versus the radiation-alone arm (44% vs. 25%). Similarly, the incidence of life-threatening side effects, including hematologic toxicity and fistula formation, was increased from 3% to 20%. In conclusion, this study demonstrated a significant improvement in local control, median and overall survival, and distant metastasis development with the addition of chemotherapy, at the cost of increased side effects.

Comparison of outcomes data from “definitive” chemoradiation approaches suggests that survival with combined chemoradiation is similar to that achieved by surgery alone. In previously discussed studies, median survivals of 14 to 20 months and 5-year survival rates of 20% to 30% were achieved with chemoradiation alone; in comparison, in the MRC trial and Intergroup trial evaluating surgery alone, median survivals were 13 to 16 months, with 5-year survivals of approximately 20%. In addition, local failure rates appear similar. For example, in the RTOG/Intergroup studies using chemoradiation therapy alone, local failure rates as a first site of failure range from 39% to 45%. In comparison, local failure rate for the Intergroup study evaluating surgery alone was 31%. However, this analysis was limited to patients undergoing R0 resection only (59% of patients).¹³⁴ This would undoubtedly be higher if all patients were considered. Therefore, local failure and survival rates appear similar between “definitive” chemoradiation and surgical approaches.

    Updated by Ramesh Rengan (11/22/2013) One approach to improve local control with “definitive” chemoradiotherapy is the addition of a radiosensitizer, such as cetuximab. Recently, the results of the SCOPE1 trial, a multicenter randomized trial of chemoradiotherapy with or without cetuximab were reported. The trial was terminated early as it met the criteria for futility. Patients who received chemoradiotherapy and cetuximab had shorter median overall survival (22.1 months vs 25.4 months p=0.035) and therefore the investigators could not recommend the addition of cetuximab to standard chemoradiotherapy for esophageal cancer. (Crosby T, Hurt CN, Falk S, et al., Lancet Oncol. 2013 Jun;14(7):627-37. [PMID: 23623280])

Chemoradiation versus Chemoradiation Followed by Surgery

Two randomized trials examined whether surgery is necessary after combined-modality therapy. A report from French investigators randomized 445 patients with clinically resectable squamous cell or adenocarcinoma of the esophagus.¹⁵¹ All patients received concurrent 5-fluorouracil and cisplatin–based chemoradiation. Patients were treated with one of two radiation regimens: 46 Gy over 4.5 weeks (continuous) or 30 Gy at 15 Gy per week (split course). Two hundred fifty-nine patients who had at least a partial response were then randomized to either surgery or additional combined-modality therapy of 5-FU and cisplatin delivered concurrent with radiation (either an additional 20 Gy at 2 Gy per day or a split course of 15 Gy). No significant difference in 2-year survival (34% vs. 40%; p = .56) or median survival (18 vs. 19 months) was seen between the groups, although 2-year local control results favored the surgical arm (66% vs. 57%). The death rate at 3 months following treatment was 9% in the surgery group versus 1% in the combined-modality therapy–alone group. In addition, patients undergoing surgery were found to have a worse quality of life. However, the rate of stent and dilatation requirement was higher in the nonsurgical arm. The results of this trial suggest that surgery after chemoradiation in responding patients does not further enhance survival.

In another study, from Germany, patients with potentially resectable squamous cell carcinoma of the esophagus received induction chemotherapy with 5-FU, leucovorin, etoposide, and cisplatin for three cycles, followed by concurrent etoposide and cisplatin with 40 Gy of external-beam radiation therapy.¹⁵² Patients were then randomized to receive surgery versus continuing with combined chemoradiation (total radiation dose increased to 60 to 65 Gy, with or without brachytherapy). Local control was significantly improved in patients undergoing surgery (2-year local control, 64% vs. 41%; p < .05). Despite this, no significant difference in survival was seen (median survival, 16 vs. 15 months; 3-year survival; 31% vs. 24%; p = NS). The “severe” postoperative complication rate (including infection, leak) was 70%, and the hospital mortality rate was 11%. Overall treatment-related mortality was significantly higher in patients undergoing surgery (13% vs. 3.5%). In patients who did not respond to induction chemotherapy, 3-year survival was improved in patients undergoing surgery (18% vs. 9%). On regression analysis, only tumor response to induction chemotherapy was found to be a significant prognostic factor. An important caveat to this trial was that only approximately two-thirds of patients in the surgery arm actually had surgery. The authors concluded that (a) surgery after combined-modality therapy improves local control but had no impact on overall survival and (b) nonresponders to induction chemotherapy may benefit from surgery, and it may be appropriate to individualize therapy based on response to induction treatment. Although it has not been well studied, retrospective experience suggested that definitive chemoradiation in patients with adenocarcinoma of the esophagus results in median survival of 21 months and 2-, 3-, and 5-year survival rates of 44%, 33%, and 20% respectively.¹⁵³

In summary, although surgery after combined chemoradiation for esophageal cancer appears to improve local control, its effect on ultimate survival is unclear.

Brachytherapy

Gaspar et al.^154,155 reported the results of a prospective trial evaluating intraluminal brachytherapy in patients with nonoperable esophageal cancer. Patients initially received 50 Gy of external irradiation with concurrent chemotherapy, followed by a 2-week break and brachytherapy administration. Patients received either 15 Gy using HDR techniques over three consecutive weeks (5 Gy/fraction) or a single administration of 20 Gy using low–dose-rate (LDR) techniques. Dose was prescribed to 1 cm from the source axis. Treatments were accomplished by placement of a 10- to 12-French applicator inserted transnasally or transorally. The target length was defined as the pretreatment tumor length with 1-cm margin proximally and distally as determined by CT, barium swallow, and endoscopy. Both external irradiation and brachytherapy were given concurrently with 5-FU chemotherapy. After the development of fistulas in six patients, the HDR dose was reduced to 10 Gy in two fractions, and the LDR arm was ultimately closed because of poor accrual. Results showed a median survival of 11 months in all patients. Local disease persistence/recurrence was observed in 63% of 49 eligible patients receiving HDR therapy. Six patients developed esophageal fistulas, resulting in three deaths. These fistulas were deemed treatment related. The 1-year actuarial fistula development rate was 18%. The investigators concluded that esophageal brachytherapy, particularly in conjunction with chemotherapy, should be approached with caution. Review of other combined brachytherapy/EBRT series suggests that fistula formation rates range from 0% to 12%, with a possible trend toward a higher incidence in patients receiving concurrent chemotherapy with brachytherapy. The incidence of brachytherapy related mortality varies from 0% to 8%, with most series reporting rates of 4% or less.¹⁵⁶

Other studies have suggested that HDR brachytherapy is effective for palliation of dysphagia in up to 90% of patients.¹⁵⁶ Danish investigators reported the results of a randomized trial of 209 patients with dysphagia due to inoperable esophageal or gastroesophageal junctional tumors.¹⁵⁷ Patients were randomized to either endoscopic stent placement or single-dose HDR brachytherapy. Patient exclusion criteria included tumors >12 cm, tumors within 3 cm of the upper esophageal sphincter, deeply ulcerated tumors, tracheoesophageal fistula/tracheal involvement, presence of a pacemaker, and previous radiation treatment or stent placement. Brachytherapy was delivered through a flexible 1-cm applicator delivering a dose of 12 Gy prescribed to 1 cm from the source axis. The treatment length was defined as gross disease plus 2 cm proximally and distally. Although trial results showed a more rapid improvement in dysphagia after stent insertion, long-term dysphagia relief was significantly improved in the group receiving brachytherapy. Patients undergoing brachytherapy experienced more days with low-grade or no dysphagia versus patients with stent placement. Complications rates were higher following stent placement (33% vs. 21%), primarily due to an increased incidence of late hemorrhage in the stent group. The authors concluded that single-dose brachytherapy is preferable to stent placement as the initial treatment for patients with progressive dysphagia due to inoperable esophageal or gastroesophageal junction carcinoma.

For patients treated with curative intent (unifocal thoracic tumors <10 cm, no distant metastases, no airway involvement or cervical esophageal location), the American Brachytherapy Society recommends a brachytherapy dose of 10 Gy in two weekly fractions of 5 Gy each (HDR) or 20 Gy in a single course at 0.4 to 1 Gy/hour (LDR). The dose is prescribed to 1 cm from mid source and delivered through a 6- to 10-mm applicator. The recommended active length is the visible mucosal tumor with a 1- to 2-cm proximal and distal margin. Ideally, brachytherapy is started 2 to 3 weeks after completion of concurrent external irradiation/chemotherapy to allow mucositis resolution. Concurrent chemotherapy with brachytherapy is not recommended. In palliative cases, a similar approach is recommended, with delivery of 10 to 14 Gy in one or two fractions (HDR) or 20 to 25 Gy in a single course (LDR). In previously untreated patients with a short life expectancy (<3 months), a dose of 15 to 20 Gy in two to four fractions (HDR) or of 25 to 40 Gy (LDR) without external irradiation is recommended (Tables 53.10 to 53.12).¹⁵⁸ In summary, the use of brachytherapy in the curative approach to esophageal cancer does not appear to significantly improve results achieved with combined external-beam radiation therapy with chemotherapy alone.

TABLE 53.10. Selection Criteria for Brachytherapy in the Treatment of Esophageal Cancer

TABLE 53.11. Suggested Schema for Definitive External Beam Radiation and Esophageal Brachytherapy

TABLE 53.12. Suggested Schema for External Beam Radiation and Brachytherapy in the Palliative Treatment of Esophageal Cancer

Palliative Treatment

Although treatment advances have occurred in esophageal cancer over the last 20 years, the majority of patients diagnosed with esophageal cancer will die of their malignancy. Therefore, palliation remains an important goal. Dysphagia is a common presenting symptom, and may significantly impair patient's quality of life. Many studies report a 60% to >80% rate of relief from dysphagia with radiation.¹⁵⁹ Coia et al.¹⁵⁹ reported that nearly half of patients with baseline dysphagia experienced an improvement in swallowing within 2 weeks of treatment initiation. By the completion of the sixth week, >80% experienced improvement. A median time to maximal improvement was approximately 1 month. Given the superior outcomes of patients receiving concurrent chemotherapy with radiation therapy in nonmetastatic disease, palliative chemoradiation is likely preferable to radiation alone for patients with advanced-stage esophageal carcinoma who have a good performance status. As described earlier, intraluminal brachytherapy has also been used for palliation of dysphagia. The previously described randomized trial from the Netherlands comparing intraluminal brachytherapy to stent placement showed that although patients undergoing stenting experienced a more rapid improvement in dysphagia, long-term palliation was significantly improved in patients treated with brachytherapy.¹⁵⁷

    Updated by Ramesh Rengan (11/22/2013) More recently, Amdal and colleagues performed a systematic review of factors associated with improved health-related quality of live (HRQL) in patient reported outcomes (PRO) in esophageal cancer patients receiving palliative chemotherapy or radiotherapy. They reported that brachytherapy resulted in better HRQL when compared to stent placement in two trials with sufficient standard of PRO reporting. (Amdal CD, Jacobsen AB, Guren MG, et al., Acta Oncol. 2013 May;52(4):679-90 [PMID: 23190360])

The palliative management of patients with tracheoesophageal fistula presents a clinical dilemma. Fistulization usually precludes surgery. These patients are often treated effective with the placement of silicone-covered, self-expanding metal stents, often obviating palliative surgery. In addition, placement of feeding gastrostomy or jejunostomy may be appropriate. Although considered a “relative” contraindication to radiation therapy, limited data from a Mayo Clinic series suggests that radiation therapy may not increase fistula severity and can be administered safely in this setting; however, the presence of fistula is a poor prognostic factor.¹⁶⁰

Treatment Sequelae

Advances in surgical technique, as well as improved preoperative and postoperative management, have decreased treatment-related mortality. Contemporary operative mortality rates are generally <10%.^152,161Complication rates can exceed 75%, including pulmonary and cardiac complications, anastomotic leak, and recurrent laryngeal nerve paralysis. Stricture formation can occur in 14% to 27% of patients. The addition of preoperative radiation therapy and chemotherapy may enhance surgical complication rates.

More than 75% of patients receiving radiation experience transient esophagitis and dysphagia, sometimes requiring some type of nutritional support. Chemotherapy-related leukopenia and thrombocytopenia are common. Additional acute toxicities of radiation therapy include esophagitis, epidermitis, fatigue, and weight loss in most patients. Nausea and vomiting are relatively common, particularly in patients with lower esophageal and gastroesophageal junction tumors. Many symptoms resolve within 1 to 2 weeks of treatment completion. A perforated esophagus is life-threatening and can be characterized by substernal chest pain, a high pulse rate, fever, and hemorrhage.⁹³ The addition of chemotherapy can significantly increase acute complications. Moderate-to-severe and even life-threatening toxicities have been reported in 50% to 66% of patients.^71,149,162 In the previously discussed RTOG study of chemoradiation alone, patients treated with combined therapy had a higher incidence of acute grade 3 (44% vs. 25%) and grade 4 toxicity (20% vs. 3%) compared to patients receiving radiation therapy alone.¹⁴⁶ Chemoradiation treatment–related mortality rates range from 0% to 3%.^{71,117,141,149,152}

The most common late effects following radiation therapy are stenosis and stricture formation. Stenosis can occur in >60% of patients. Stricture requiring dilatation has been reported to occur at least 15% to 20% of the time. Dysphagia may be relieved with two to three dilatations.⁷¹ Long-term results from the RTOG study showed that late grade 3 or greater toxicity was similar in the combined versus radiation-alone arms (29% vs. 23%). However, grade 4 or greater toxicity was higher in patients receiving combined-modality therapy (10% vs. 2%).¹⁵⁰ Other complications include clinically apparent damage to organs within the radiation therapy volume, although this is uncommon. Chemotherapy may further increase the risk of late treatment-related toxicities.

The effects of radiation on pulmonary and cardiac function deserve special mention. Pulmonary complications associated with either the definitive or neoadjuvant treatment of esophageal cancer patients can be broadly broken up into symptomatic pneumonitis following treatment completion and postoperative pulmonary complications in patients undergoing resection. Although they are still ill defined, various institutional series have described predictive factors for these complications (which are not mutually exclusive), which are described in the following.

Radiation pneumonitis is a relatively common complication in the treatment of thoracic (lung) malignancies, with can range from minimally symptomatic to fatal. Common symptoms include nonproductive cough, dyspnea, and, more uncommonly, respiratory distress. Generally, this occurs 2 to 6 months after radiation therapy completion. The ability to predict radiation pneumonitis has been a significant topic of investigation. However, most data come from patients with lung cancer, who may have more underlying intrinsic pulmonary/smoking-related disease. A variety of predictive parameters have been suggested, including V₂₀ of >25%–30%, mean lung dose of >15 to 20 Gy, V₅ of >42%, and absolute V₅ of >3,000 cm³.¹⁰⁷

In nonoperative patients, an analysis of esophageal cancer patients from Japan treated definitively to a dose of 60 Gy with concurrent 5-FU and cisplatin showed a radiation pneumonitis incidence of 27%.¹⁶³ The authors concluded that an optimal V₂₀ threshold to predict symptomatic pneumonitis was approximately 30%. In a study of 101 both operative and nonoperative patients (88% distal esophagus/GE junction) from the MD Anderson Cancer Center undergoing a mix of 3D and IMRT radiation therapy, 59%, 5%, and 1% of patients experienced grade 2, 3, and 5 radiation pneumonitis, respectively.¹⁶⁴ An analysis from Japan using fields inclusive of supraclavicular, mediastinal, and celiac regions up to a dose of 60 Gy with concurrent cisplatin and 5-FU showed a 2-year cumulative incidence of late, high-grade cardiopulmonary toxicities for patients ≥75 years of 29% versus 3% in younger patients. They concluded that older patients may not tolerate extensive radiation fields.¹⁶⁵ Other studies have shown that significant declines in diffusion capacity and total lung capacity may occur in patients irradiated for esophageal cancer.¹⁶⁶

In operative patients, a study of 110 patients treated with preoperative chemoradiotherapy followed by resection at the MD Anderson Cancer Center showed that mean lung dose, effective dose, and absolute lung dose receiving ≤5 Gy were predictors of development of postoperative pulmonary complications.¹⁶⁷ In a report on patients from the same institution describing complications in patients receiving neoadjuvant combined modality therapy,¹⁶⁸ 18% experienced pulmonary complications, with higher rates when the V₁₀ was ≥40% (35% vs. 8%) and V₁₅ was ≥30% (33% vs. 10%), leading the authors to conclude that minimization of lung volume irradiation was important in the preoperative planning of these patients. This increase in postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome) when the V₁₀ was >40% suggests that the volume of remaining/undamaged functional lung may determine postoperative pulmonary function, that is, patients with a small lung volume initially may be at higher risk of experiencing pulmonary complications, even if the relative V₅ is low, and that patients with small lung volume with less functional reserve may be more susceptible to postoperative pulmonary complications. Therefore, it is important to consider not only the dose–volume histogram of the lung, but also the total lung volume.

A study from China evaluating patients receiving chemoradiotherapy followed by resection showed that the volume of lung spared from doses of ≥5 Gy was the only independent dosimetric factor on multivariate analysis in predicting postoperative pulmonary complications.¹⁶⁹ Wang et al.¹⁷⁰ similarly described that the relative V₅ and all spared volumes from 5 to 35 Gy significantly correlated with the incidence of postoperative pulmonary complications, although on multivariate analysis, V₅ was the only significant independent predictive factor, indicating that the volume of “unexposed” lung during induction therapy was predictive. Of note in this study was that the majority of patients were treated with induction chemotherapy alone initially (most paclitaxel), which has been shown to increase rates of pneumonitis in other disease sites. A significant association of induction chemotherapy alone prior to concurrent chemoradiotherapy was seen as a predictor of grade 2 or greater pneumonitis (49% vs. 14%; p = .003), leading the authors to conclude that induction chemotherapy alone may sensitize lung tissue to radiation damage. In contrast to the foregoing studies, however, another analysis of 98 patients receiving preoperative chemoradiotherapy with 5-FU and cisplatin showed no difference in pulmonary complications versus patients undergoing surgery alone, with no correlation of any lung dose–volume histogram findings with development of postoperative pulmonary complications seen, leading the authors to conclude that neoadjuvant chemoradiotherapy had no detrimental impact on postoperative course.¹⁷¹ Finally, an analysis from Taiwan of neoadjuvantly, IMRT-treated esophageal cancer patients undergoing resection suggested that preoperative (not prechemoradiation) forced expiratory volume in 1 second was an independent factor associated with postoperative pulmonary complications and that reducing the absolute volume of the right lung irradiated might decrease the risk of postoperative pulmonary complications.¹⁷²

Radiation-induced cardiac toxicity is a broad term describing potential radiation injury to a number of cardiac structures, including pericardium (as manifested by effusion, pericarditis), coronary arteries, the heart muscle itself, and cardiac valves, as well as nerve/conduction injury. Radiation injury primarily consists of fibrosis and/or small-vessel injury. “Classic” radiation tolerance (TD5/5) of the heart is about 60 Gy when 25% or less of the heart is irradiated and 45 Gy if 65% of the heart is irradiated, assuming 2 Gy per fraction. The mechanism of radiation-induced cardiac injury is relatively poorly defined, particularly in the context of esophageal cancer. Historical data from the treatment of Hodgkin's disease patients suggest that a dose of >40 Gy may increase the risk of cardiac death, as well as of pericarditis.^173,174 Several studies of cardiac toxicity and esophageal cancer patient demonstrated that a V₃₀ of >46% predicted a significant increase in pericardial effusion, and increasing fraction size (particularly ≥3.5 Gy) also predicted the same. In addition, some authors have shown a possible trend for decrease in ejection fraction in patients with increasing V₂₀ of the left ventricle.¹⁰⁷ In a study of 150 esophageal cancer patients receiving chemoradiotherapy (49 neoadjuvantly), the incidence of pericardial effusion was 28%, usually developing within 15 months of radiation therapy, with median onset time of approximately 5 months. The risk of pericardial effusion was associated with mean pericardial doses over an array of dose–volume points to the pericardium from 5 to 45 Gy. A matched-pair analysis of nonradiation patients receiving surgery versus those treated neoadjuvantly was performed, with 42% of patients in the radiation group demonstrating ischemia/scarring on single-photon emission computed tomography images versus 4% in the surgical group, with a median onset to abnormality of 3 months.¹⁷⁵ In a Japanese study, long-term analysis of 139 patients treated with definitive chemoradiotherapy (cisplatin/5-FU with 60 Gy EBRT) for squamous cell carcinoma revealed grade 2, 3, and 4 late pericarditis occurring in 6%, 5%, and 1% of patients, respectively; grade 4 heart failure in 2 patients; grade 2, 3, and 4 pleural effusion development in 5%, 6%, and 0% of patients, respectively; and grade 2, 3, and 4 radiation pneumonitis development in 1%, 2%, and 0% of patients, respectively.¹⁷⁶

Future Considerations

Although modest improvements in survival have been achieved by combining neoadjuvant chemoradiation and surgery, patients treated with chemoradiation alone or with surgery have unacceptably high local-regional relapse rates and mortality rates. Ultimately, approximately 75% of patients succumb to metastatic disease. As described previously, efforts at radiation dose escalation have not resulted in significant gains for this disease. Given these data, clinical trials have turned to studies evaluating new and potentially more effective chemotherapeutic agents with radiation therapy. Agents such as irinotecan, oxaliplatin, capecitabine, epirubicin, gemcitabine, and docetaxel have been or are being investigated in the metastatic setting, as well as “curative” settings in combination with radiation therapy. Furthermore, there is ongoing investigation of the use of the vascular endothelial growth factor inhibitor bevacizumab, the HER2/neu receptor antagonist trastuzumab, and inhibitors of the epidermal growth factor receptors, including the antibodies cetuximab and panitumumab, in the treatment of esophageal cancer. All of these agents have radiosensitizing properties. The investigation of these agents with radiation therapy is the subject of ongoing and future trials.

Summary

The prognosis for patients with carcinoma of the esophagus remains poor despite recent advances in combined-modality therapies. No firm recommendation can be made for managing locally advanced disease. The data suggest that neoadjuvant chemoradiation improves outcomes in patients who are candidates for surgery. Alternatively, randomized trials have also suggested that perioperative chemotherapy improves outcomes in these patients. However, many patients are not able to tolerate surgery, and combined chemoradiation may be more appropriate in selected patients because definitive chemoradiation has resulted in survival rates comparable to those from surgery alone. Locoregional failure remains a significant pattern of relapse. For patients with stage IV disease, palliation with single-modality therapy or several modalities should be used and tailored to the patient's specific symptoms. Current unresolved issues include the following:

1. Which subsets of patients are more likely to benefit from the addition of surgery than others?
2. Which subsets of patients are more likely to benefit from the addition of neoadjuvant and/or perioperative therapies?
3. Can introduction of newer chemotherapy/targeted agents in the neoadjuvant or concurrent setting improve the results over “standard” chemoradiation with cisplatin and 5-FU?
4. Will new technologies such as 3D conformal therapy, PET-based planning, intensity-modulated radiation therapy, proton therapy, and image-guided radiation therapy decrease complication rates and influence cure rates?
5. Will PET scan allow early prediction of both response to treatment and ultimate outcomes and potentially allow avoidance of delivery of ineffective treatments early on during the course of therapy?
6. Will the identification of molecular prognostic markers allow “individualization” of treatments among patients?
7. In surgical patients, is there a superiority of a neoadjuvant chemoradiation versus a perioperative chemotherapy approach, and will some patients benefit from one particular treatment approach?